Methods of treating cardiac arrhythmia

ABSTRACT

Methods and apparatus of embodiments of the invention are adapted to treat tissue inside a patient&#39;s body. Aspects of the invention can be used in a wide variety of applications, but certain embodiments provide minimally invasive alternatives for treating atrial fibrillation by delivering a tissue-damaging agent to selected areas of the heart. One exemplary embodiment of the invention provides a method of treating cardiac arrhythmia. This method includes positioning a distal tissue-contacting portion of a body in surface contact with a tissue surface of cardiac tissue; detecting the surface contact between the tissue-contacting portion and the tissue surface; and thereafter, injecting a tissue-ablating agent into the cardiac tissue through the tissue-contacting portion of the body.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/591,126, filed Oct. 31, 2006, which is a divisional of U.S. patentapplication Ser. No. 10/099,528, filed Mar. 14, 2002, which claimspriority to the following U.S. patent applications, each of which isincorporated herein by reference in its entirety: U.S. ProvisionalPatent Application No. 60/137,265, filed Jun. 2, 1999; U.S. patentapplication Ser. No. 09/585,983, titled “Devices and Methods forDelivering a Drug” filed Jun. 2, 2000; International Application No.PCT/US00/115386, titled “Devices and Methods for Delivering a Drug”filed Jun. 2, 2000 (which was published in English Dec. 7, 2000 asInternational Publication No. WO 00/72908); U.S. Provisional PatentApplication No. 60/275,923, titled “Sensor Device and Apparatus forAffecting a Body Tissue at an Internal Target Region” filed Mar. 14,2001; U.S. Provisional Patent Application No. 60/327,053, titled “Methodand Apparatus for Guided Interventional Procedures” filed Oct. 3, 2001;and U.S. Provisional Patent Application No. 60/340,980, titled “Methodand Apparatus for Treatment of Atrial Fibrillation” filed Dec. 7, 2001.

FIELD OF THE INVENTION

Embodiments of the invention relate generally to medical procedures andinterventional medical devices that can be used to treat cardiacarrhythmias and other conditions. Many of these embodiments haveparticular utility in treating atrial fibrillation.

BACKGROUND OF THE INVENTION

A wide variety of diseases and maladies can be treated by surgicalintervention. Increasingly, however, less invasive procedures are soughtto achieve similar objectives while reducing risks and recovery timeassociated with more traditional surgical approaches. For example, avariety of thoracic surgical procedures, such as treatment of aorticaneurysms and arterial stenosis, were traditionally performed via agross thoracotomy. Less invasive procedures, such as balloon-expandedstents and PTCA, have been developed which avoid the need for a grossthoracotomy, requiring instead only a small incision to gain access tothe thoracic cavity intravascularly or through an intercostal opening.

Cardiac arrhythmias present a significant health problem. Cardiacarrhythmias include ventricular tachycardias, supra ventriculartachycardias, and atrial fibrillation. Of these, atrial fibrillation isthe most common cardiac arrhythmia. It has been estimated that over onemillion people in the United States alone suffer from atrialfibrillation. Incidence of atrial fibrillation is expected to increaseover the next several decades as populations in the United States andEurope trend older because atrial fibrillation tends to become morecommon with increasing age.

Atrial fibrillation may be treated with medication intended to maintainnormal sinus rhythm and/or decrease ventricular response rates. Not allatrial fibrillation may be successfully managed with medication, though.A surgical approach was developed to create an electrical maze in theatrium with the intention of preventing the atria from fibrillating.Known, appropriately, as the “maze” procedure, this technique involvesmaking atrial incisions which interrupt pathways for reentry circuitswhich can cause atrial fibrillation and instead direct the cardiacelectrical impulse through both atria before allowing the signal toactivate the ventricles. As a result, virtually the entire atrialmyocardium, with the exception of the atrial appendages and thepulmonary veins, can be electrically activated. The maze procedure isvery effective in reducing or eliminating atrial fibrillation.Unfortunately, the procedure is difficult to perform and hastraditionally required a gross thoracotomy and cardiopulmonary bypass topermit the surgeon appropriate access to the patient's heart.

Several less invasive techniques have been proposed for achieving asimilar maze-like effect in the atrial myocardium without requiringdirect surgical intervention. For example, U.S. Pat. No. 6,267,760(Swanson) and U.S. Pat. No. 6,237,605 (Vaska et al.), both of which areincorporated entirely herein by reference, suggest RF ablation devicesintended to ablate cardiac tissue and create atrial myocardial lesionsto achieve much the same purpose as the surgical incisions of thestandard maze procedure. U.S. Pat. No. 6,161,543 (Cox et al.), which isalso incorporated entirely herein by reference, suggests that acryogenic probe be employed to freeze tissue instead of using the RFablation devices to heat tissue. Each of these approaches leavessomething to be desired, however.

SUMMARY OF THE INVENTION

Embodiments of the present invention provide methods and apparatusadapted to treat tissue inside a patient's body. Some of the embodimentsof the invention can be used in a wide variety of applications to treata number of diseases or conditions. For example, embodiments of theinvention can be used to accurately deliver a therapeutic agent (e.g.,DNA for gene therapy) to a diseased tissue or deliver an angiogenicsubstance to induce angiogenesis in hypoxic tissue.

One embodiment of the invention provides a medical device adapted totreat patient tissue which includes a fluid reservoir, a tissuecontacting member, and a fluid delivery conduit. The tissue contactingmember is adapted to be manipulated into contact with a surface of atarget tissue. It also includes a body, first and secondtissue-contacting surfaces spaced from one another to define a gaptherebetween, and a recess proximate to the gap. The fluid deliveryconduit is in fluid communication with the reservoir and has a pluralityof outlet ports. A length of the fluid delivery conduit is received inthe recess with the outlet ports oriented toward, but spaced from, thegap.

Another embodiment of the invention provides an alternative medicaldevice which includes a fluid reservoir, a tissue grasping member, andfirst and second fluid delivery conduits in fluid communication with thereservoir. The tissue grasping member has a first tissue contactingmember and an opposed second tissue contacting member. The first andsecond tissue contacting members are operatively associated with oneanother and movable between a first configuration wherein they have afirst relative orientation adapted to receive the tissue therebetweenand a second configuration wherein they have a second relativeorientation adapted to grasp tissue therebetween. The first fluiddelivery conduit has a distal length carried by the first tissuecontacting member and a plurality of outlet ports spaced along thatdistal length. The second fluid delivery conduit has a distal lengthcarried by the second tissue contacting member and a plurality of outletports spaced along that distal length. The outlet ports of the first andsecond fluid delivery conduits are oriented generally inwardly towardone another when the tissue grasping member is in the secondconfiguration.

A method in accordance with an embodiment of the invention can be usedto create a line of ablated tissue on a hollow organ or vessel havingopposed walls. While this organ may comprise the heart, other organs orbody vessel may be treated with this method, as well. The opposed wallsof the organ are brought closer together, but not in contact with oneanother, along a distance within a plane. Tissue in the opposing wallsis ablated along the plane to form a corresponding line of ablatedtissue through the opposed walls.

A number of embodiments of the invention are particularly well suitedfor use in treating cardiac arrhythmias. In certain embodiments, theinvention provides a minimally invasive alternative for treating atrialfibrillation by delivering a tissue-damaging agent to selected areas ofthe heart.

One such embodiment provides a medical device that can be used for,among other things, treating cardiac arrhythmia. This medical deviceincludes a reservoir for an injectable tissue-ablating agent. The devicemay also include an elongate body adapted for introduction into athoracic cavity. The body may have a distal tissue-contacting memberhaving a length that is flexible and adapted to conform to a surface ofa target tissue. A plurality of outlet ports is spaced along thetissue-contacting member and a lumen in the body communicates the fluidsupply with the outlet ports. A pressure control is in fluidcommunication with the reservoir and is operable to establish anelevated pressure within the lumen and propel the tissue-ablating agentfrom the fluid supply through the outlet ports to define a plurality ofspaced-apart fluid jets capable of penetrating the target tissue.

A method of treating cardiac arrhythmia in accordance with a differentembodiment of the invention may include positioning a tissue graspingmember adjacent a target tissue of a heart atrium or a pulmonary vein.The target tissue has two spaced-apart wall segments. Opposedtissue-contacting members of the tissue grasping member may be movedtoward one another to deform the target tissue such that the wallsegments are moved closer to, but remain spaced from, one another.Target tissue in contact with the tissue contacting members may beablated to create a lesion extending through both wall segments.

Still another embodiment of the invention provides a method of at leastpartially electrically isolating a pulmonary vein from a heart atriumhaving two spaced-apart wall segments. In this method, the two wallsegments are juxtaposed along a first plane. Tissue in both wallsegments is ablated along the first plane with an ablating member toform a lesion along a first length of each wall segment. The ablatingmember may be moved and the two wall segments may be juxtaposed along asecond plane, which may coincide with the first plane. Tissue in bothwall segments is ablated along the second plane with the ablating memberto form a lesion along a second length of each wall segment, the secondlength adjoining the first length.

In an alternative embodiment of the invention for treating cardiacarrhythmia, a body of an injectate delivery device is guided within apatient's thoracic cavity to position a distal tissue-contacting portionof the body in surface contact with a tissue surface of cardiac tissue.Surface contact between the tissue-contacting portion and the tissuesurface is detected. Thereafter, a tissue-ablating agent (e.g., analcohol, hypertonic saline, or suitably hot or cold saline) is injectedinto the cardiac tissue through the tissue-contacting portion of thebody. If so desired, the surface contact may be detected by supplying anexcitation voltage to a plurality of electrodes positioned on thetissue-contacting portion of the body and measuring a level of at leastone current conducted by the plurality of electrodes. This level maydepend upon a degree of contact between at least two of the electrodesand the tissue surface.

In accordance with another embodiment, a method of treating atrialfibrillation includes guiding an elongate, flexible body into proximitywith an exterior tissue surface of a predetermined portion of a cardiactissue. An elongate tissue-contacting portion of the body is broughtinto surface contact with the tissue surface. This tissue-contactingportion may include a plurality of electrodes and a level of at leastone current conducted by the plurality of electrodes may be measured,with the current level depending on a degree of contact between at leasttwo of the electrodes and the tissue surface. Thereafter, atissue-ablating fluid may be injected into the cardiac tissue throughthe tissue-contacting portion of the body, creating a signal-impedinglesion in the cardiac tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of an embodiment of a catheter apparatus.

FIG. 2 is a diagram of an embodiment of a catheter apparatus.

FIG. 3A is a diagram of the distal end of an embodiment of an apparatusshowing the relative position of the distal end to body tissue.

FIG. 3B is a diagram of the distal end of an embodiment of an apparatusshowing the relative position of the distal end to body tissue.

FIG. 3C is a diagram of the distal end of an embodiment of an apparatusshowing the relative position of the distal end to body tissue.

FIG. 3D is a diagram of the distal end of an embodiment of an apparatusshowing the relative position of the distal end to body tissue.

FIG. 3E is a diagram of the distal end of an embodiment of an apparatusshowing the relative position of the distal end to body tissue.

FIG. 4A is an end view of an embodiment of a probe with sensors.

FIG. 4B is a cross-sectional view of an embodiment of a probe withsensors.

FIG. 5A is a diagram of an embodiment of a probe with sensors, showingthe relative position of the probe and the sensors to body tissue.

FIG. 5B is a graph of current as a function of percentage of contactbetween sensors and body tissue.

FIG. 6A is an end view of an embodiment of a probe with sensors.

FIG. 6B is a cross-sectional view of the embodiment of FIG. 6A.

FIG. 7A is an end view of an embodiment of a probe with sensors,illustrating partial contact between the sensors and body tissue.

FIG. 7B is a diagram of an embodiment of a display that indicatespartial contact between sensors and body tissue.

FIG. 8A is an end view of an embodiment of a probe with sensors.

FIG. 8B is a cross-sectional view of an embodiment of a probe withsensors.

FIG. 8C is a cross-sectional view of an embodiment of a probe withsensors.

FIG. 9A is a diagram of an embodiment of a probe with sensors partiallyintruding into body tissue.

FIG. 9B is a graph of current as a function of percentage of contactbetween sensors and body tissue.

FIG. 10A is an end view of an embodiment of a probe with sensors.

FIG. 10B is a cross-sectional view of an embodiment of a probe withsensors.

FIG. 11A is a diagram of an embodiment of a probe with sensors partiallyintruding into body tissue such that the probe is not perpendicular tothe body tissue surface.

FIG. 11B is a diagram of a display of one embodiment that indicates theposition of the probe with respect to the body tissue surface and adegree of intrusion into the body tissue.

FIG. 12A is a cross-sectional view of an embodiment of a probe with aworking element and sensors, showing the working element in a retractedposition.

FIG. 12B is a cross-sectional view of an embodiment of a probe with aworking element and sensors, showing the working element in an extendedposition.

FIG. 13 is a cross-sectional view of an embodiment of a probe with aworking element and sensors, showing the working element in a retractedposition.

FIG. 14 is a cross-sectional view of an embodiment of a probe with aworking element that is a sensor.

FIG. 15 illustrates a steerable catheter-type device for deliveringselected diagnostic and/or therapeutic agents to target sites within aselected body tissue using high-energy jets, in accordance with anembodiment of the present invention.

FIG. 16A is an enlarged, side-sectional view of a distal-end region ofthe device shown in FIG. 15.

FIG. 16B shows the device of FIGS. 15 and 16A being used to direct fourhigh-energy jets carrying one or more selected therapeutic and/ordiagnostic agents through a wall of a selected body organ and into thetissue.

FIG. 17 is an exploded view of the apparatus of FIGS. 16A-B.

FIG. 18 is a partial, side-sectional view of a further embodiment of anagent-delivery apparatus for delivering selected diagnostic and/ortherapeutic agents to target sites within a selected body tissue usinghigh-energy jets, according to the teachings of the present invention.

FIG. 19 shows the distal-end region of a steerable catheter-type devicefor delivering selected diagnostic and/or therapeutic agents to targetsites within a selected body tissue using ultrasonic energy, accordingto one embodiment of the present invention.

FIG. 20A shows, in partial side-sectional view, an exemplaryagent-delivery port and a secondary drug or gas port that meets thedelivery port at an angle, as well as several exemplary jet or spraypatterns.

FIGS. 20B-D schematically illustrate exemplary jet or spray patternswhich may be achieved using the apparatus of FIG. 20A.

FIG. 21 is a partial side view, with portions shown in section, of anexemplary valving mechanism operable to regulate fluid flow through anagent-delivery lumen and/or outlet port.

FIG. 22 shows a portion of a steerable catheter positioned with itsdistal end adjacent a target region of an endocardial wall of apatient's left ventricle, with the catheter being adapted to maintainits distal end at such position notwithstanding “action-reaction” forcesdue to high-energy jets emanating therefrom that would tend to push itaway from the wall.

FIGS. 23A-D are partial side view of examples of the invention as it isplaced near a tissue (FIG. 23A), urged against the tissue (FIG. 23B)thus creating a contact force between the device and the tissue, theapplication of hydraulic force causing ejection of a fluid stream fromeach outlet port thus propelling the fluid into the tissue (FIG. 23C),and the removal of hydraulic force and the retention of fluid by thetissue within pockets created by hydraulic erosion (FIG. 23D).

FIG. 24 illustrates an example of the invention where the device isconveyed to the target tissue via a steerable catheter with having anaxial lumen where the device is slidably directed towards the targettissue.

FIG. 25 illustrates an example of the invention where the device iscombined with a steerable catheter in one structure.

FIG. 26 illustrates an example of the invention where the device iscombined with a first steerable catheter in one structure which residesin a second steerable catheter having an axial lumen where the firststeerable catheter is slidably maintained.

FIG. 27A is an end view of an injection device incorporating tissuecontact sensors.

FIG. 27B is a cross-sectional view of the injection device of FIG. 27A.

FIGS. 28A-C are top, lateral and front views, respectively, of a tissuetreatment device in accordance with still another embodiment of theinvention having a flexible tissue-contacting member.

FIGS. 29-32 are top views of tissue treatment devices havingtissue-contacting members in accordance with other embodiments of theinvention.

FIG. 33 is a top view of another embodiment of a tissue treatmentdevice.

FIG. 34 is a partial side view of the tissue treatment device of FIG. 33taken along line 34-34 in FIG. 33.

FIG. 35 is a schematic cross sectional view of the tissue treatmentdevice of FIGS. 33-34 taken along line 35-35 in FIG. 34.

FIG. 36 is a schematic illustration of the device of FIG. 33 being usedto treat tissue of a pulmonary vein.

FIG. 37A is a side view of a tissue treatment device in accordance withstill another embodiment of the invention.

FIG. 37B is a side view of a modified version of the embodiment of FIG.37A.

FIGS. 38A and 38B are isolation views of a distal portion of the tissuetreatment device of FIG. 37A in an open configuration and in a closedconfiguration, respectively.

FIGS. 39A and 39B are isolation views of an alternative distal portion,useful in the tissue treatment device of FIG. 37A, in an openconfiguration and in a closed configuration, respectively.

FIG. 40 is a side view of a tissue treatment device in accordance withstill another embodiment of the invention.

FIG. 41 schematically illustrates positioning of the tissue treatmentdevice of FIG. 33 adjacent to a patient's heart to treat atrialfibrillation.

FIG. 42 is a close-up view schematically illustrating a step in aprocess of forming a lesion around a pulmonary vein.

FIG. 43 schematically illustrates the lesion formed in the processillustrated in

FIG. 42.

FIG. 44 schematically illustrates positioning of an alternative tissuetreatment device with respect to two pulmonary veins.

FIG. 45 schematically illustrates the lesion formed in the processillustrated in FIG. 44.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Various embodiments of the present invention provide medical devicesthat can be used in a wide range of applications and several methodsthat can be used for, among other things, treating cardiac arrhythmia.The following description provides specific details of certainembodiments of the invention illustrated in the drawings to provide athorough understanding of those embodiments. It should be recognized,however, that the present invention can be reflected in additionalembodiments and the invention may be practiced without some of thedetails in the following description. In the following discussion,embodiments of the invention employing tissue contact sensors arediscussed first, followed by embodiments including needles, embodimentsproviding for needleless injection, and treatment methods in accordancewith embodiments of the invention.

Embodiments Including Tissue Contact Sensor(s)

Certain embodiments of the invention provide medical apparatus includingsensors that accurately indicate the position of the apparatus inrelation to body tissue. The sensors may provide this indication withoutsecondary sources of information, such as previously developed maps ofbody regions. In certain embodiments, the sensors that provide theposition information further provide physiological information. Thesensor or sensors may be placed on various locations on the cathetershaft and on the distal tip, depending on the application and desiredinformation required for the surgical or diagnostic procedure. In oneembodiment, the sensors are electrodes that indicate a degree of contactbetween the apparatus and a tissue surface, and also indicate anorientation of the apparatus with respect to the tissue surface. Thesensors further transmit an EKG signal from the body tissue. Theindication of the degree of contact includes a pressure indication, oran indication of the degree the apparatus intrudes into the body tissue.In one embodiment, a working element includes a sensor. For example, inone embodiment, the working element is a needle that delivers a drug andalso transmits an EKG signal such that the condition of the tissue ismonitored before and after the drug is delivered. In one embodiment, theapparatus includes a catheter with sensors on a distal probe forpositioning the distal probe, and a working element with a sensordisposed in a lumen of the catheter.

FIG. 1 is a diagram of an embodiment of an apparatus 14 for guidedinterventional procedures. The apparatus 14 includes an assembly 16 foraccessing a body tissue surface 18 inside a patient's body, and anactuator 24. The actuator 24 is attached to the assembly 16 in such away as to steer the assembly 16 by one of several known methods. Adistal end probe 22 is placed in contact with the tissue surface 18 inorder to perform an interventional procedure. Sensors (not shown in thefigure) in the distal probe 22 are electrically connected to a controlunit 28. The control unit 28 includes a power source for supplyingvoltage across the sensors, and circuitry for receiving and processingsignals. For example, the control unit 28 includes circuitry fordetecting and measuring current levels across the sensors.

The control unit 28 is connected to an activator 30 and a display 32.The control unit 28 is further connected to the actuator 24. In oneembodiment, the actuator 24 is automatically controlled depending uponsignals received from the sensors by the control unit 28. For example,the actuator 24 is directed to move the distal end probe or to stopmoving the distal end probe 22 dependent upon a predetermined relativeposition of the distal end probe 22 with respect to the tissue surface18. The display 32 displays information about the relative position,such as the angle of the distal end probe 22 with respect to the tissuesurface 18 and the degree of intrusion of the distal end probe 22 intothe tissue surface 18. In one embodiment, the display 32 furtherpresents EKG information.

In one embodiment, the assembly 16 is a known steerable catheterassembly. In one application, the assembly 16 is used to access aninternal target tissue region, and to provide a therapeutic stimulus.The therapeutic stimulus can be any of several known stimuli, such asinjection of a therapeutic compound, cells, or gene, forming a laserchannel, or introducing an injury on or below the surface of the targetregion. Ultrasonic waves, infrared radiation, electromagnetic radiation,or mechanical means, for example, can introduce the injury. In oneembodiment useful for treatment of atrial fibrillation, an ablativeagent or other tissue-damaging fluid may be injected through and/orbelow the surface of the target tissue. The therapeutic stimulus may beadministered/provided through the distal end probe 22.

In one embodiment, the assembly 16 is sized to be manipulated throughthe vasculature of a patient until the distal end probe 22 is proximatea surface or wall region of a selected tissue or organ. For example, thedistal end probe 22 may be placed within about 5 mm of a tissue surfacewithin a heart chamber, such as the heart endocardial wall within theleft ventricle.

In embodiments used for procedures that include injecting a compound orgene into tissue, the actuator 24 includes a drug delivery module. Thedrug can be delivered by a needle or by a needleless injection mechanismin the distal end probe 22.

In various embodiments, the assembly 16 is an endoscopic device having adistal end probe and a distal end working element (not shown) forintroducing or providing a therapeutic effect at or adjacent an organ ortissue target site. Also contemplated is a rigid accessing tool (notshown) that includes an elongate rod that can be guided through anincision, such as in the chest wall, for placement of a distal end probecarried on the rod against the surface of the target tissue.

FIG. 2 is a diagram of an embodiment of an apparatus 15 for guidedinterventional procedures that includes separate display devices forposition information and for physiological information. The apparatus 15includes the assembly 16 and the actuator 24. The apparatus furtherincludes the control unit 28 and the activator 30. The display 37displays position information from sensors as described below. Thedisplay 39 displays EKG information. In one embodiment, the display 39is a commercially available EKG monitor. In one embodiment, the display37 and the display 39 receive the same signal and filter out unneededsignal components. In one embodiment, the signal is one or more currentlevels from electrode sensors, as described below.

FIG. 3A is a diagram showing the distal end probe 22 and the tissuesurface 18. The tissue surface 18 is part of a target region of cardiactissue 34, e.g., a heart interior wall or exterior wall. A heart-walltrabecula 38 is also shown. Heart-wall trabeculae are typically about2-3 mm in diameter and have a depth of 1.5 to 2 mm. As an example of anapplication, the target region can be a hypoxic region identified aslacking sufficient oxygen, presumably due to poor vascularization in theregion. The therapeutic objective is to stimulate angiogenesis in thehypoxic region by introducing an angiogenic agent and/or by stimulatingthe tissue with an angiogenic injury. The tissue surface 18 in thisexample may comprise part of a heart chamber wall. The heart chamber maybe filled with blood in contact with the tissue surface 18. A secondexample is the injection of cells for tissue regeneration in aninfarcted region of the heart. In accordance with another embodimentuseful in treating cardiac arrhythmia, particularly atrial fibrillation,the cardiac tissue 34 shown in FIGS. 3A-E may comprise a portion of anatrial wall. For example, the cardiac tissue 34 may be located adjacenta pulmonary vein such that forming a cardiac lesion at the site couldhelp electrically isolate a pulmonary vein.

The sensors and the control unit (neither of which are shown in FIG. 3)can be used to detect that the distal end probe 22 probe is properlyplaced with respect to the tissue surface when the therapy is delivered.Optimal placement of distal end probe 22 has several components. Forexample, the distal face of the distal end probe may be in contact with,or very close to, the tissue surface 18 in the target region receivingthe treatment to more effectively control the level of therapeuticstimulus being delivered.

FIG. 3A illustrates a situation in which the distal end probe 22 is inthe chamber but not in contact with the heart wall 34. In many methodsof the invention, the therapeutic stimulus should not be applied in thissituation.

FIG. 3B illustrates the angle of contact a between the distal end probe22 and the tissue surface 18. This is another component of optimaldistal end probe 22 placement. The angle of contact a should be within adesired range, e.g., no more than 10.degree.-30.degree., with respect toan axis 40 that is normal to the tissue surface 18. Typically, as theangle a increases, the distal end probe 22 is less in contact with thetissue surface 18, and consequently the therapeutic stimulus isdistributed over a wider area rather than being concentrated in thetarget region. If the therapeutic stimulus comprises a tissue-damagingagent for use in creating lesions to treat cardiac arrhythmia, forexample, dispersing the agent over a wider or less precisely controlledarea may lead to collateral tissue damage.

Optimal placement of the distal end probe 22 can be complicated by thepresence of trabecula 38 or other irregularities on the heart wall 34,as illustrated in FIG. 3C. FIG. 3C shows initial contact of the probewith trabecula 38, which is essentially a recessed area in the targetregion. In this case, the distal end probe 22 makes contact with thetarget region, and even intrudes into the target region, but contactbetween the distal face of the distal end probe 22 and the tissuesurface 18 is limited. As will be explained below, this limited contactmay be detected and avoided using embodiments of the apparatus 14.

FIG. 3D illustrates a surface contact condition between the distal endprobe 22 and the tissue surface 18 that is optimal for certainprocedures. In this illustrated condition, the longitudinal axis of thedistal end probe 22 is substantially perpendicular to the plane of thetissue surface 18. For some procedures to be most effective, the distalend probe 22 should be applied to the tissue surface 18 with a forcethat is within a predetermined optimal range.

The depth of intrusion of the distal end probe 22 into the tissuesurface 18 is another factor that can effect optimal distal end probe 22placement. FIG. 3E shows the distal end probe 22 intruding into thetissue surface 18 in the target region. The tissue surface 18 in thetarget region is distorted as a result. In addition, the thickness ofthe heart wall is reduced locally. The tissue distortion may adverselyaffect the application of the stimulus, and the reduced tissue thicknessmay lead to suboptimal targeting of the stimulus.

Achieving a desired contact angle and contact force is furthercomplicated in the heart by the beating of the heart. In one embodiment(not shown), the heart wall movement is compensated for by a mechanismnear the distal end probe 22 that accommodates movement in multiple axeswith little change in contact angle and pressure. In other embodiments,the distal end probe is flexible so as to allow movement in multipleaxes. In various embodiments, the procedure includes timing the deliveryof the therapy to coincide with a defined period of the cardiac cyclewhen optimal contact occurs.

FIG. 4A is an end view of an embodiment of a distal end probe 42 thatallows surface contact between the distal end probe 42 and a tissuesurface to be sensed during a procedure. The distal end probe 42includes a lumen 44 through which a therapeutic stimulus can beadministered. A planar front face 46 may be placed in contact with thetarget tissue when the stimulus is administered. Inner and outer annularelectrodes, or sensors, 48 and 50, respectively, surround the lumen 44and are separated by insulators 52, 54, and 56. In one embodiment, theelectrodes 48 and 50 are formed of gold, silver, or another conductivematerial, and are formed on the probe face by plating or attachmentmethods.

In describing the operation of the electrodes, it is useful to considereach electrode as being made up of multiple electrode surface elements,such as electrode elements 62 in electrode 48 and correspondingelectrode elements 64 in electrode 50. The electrode elements havearbitrarily defined sizes and positions on their respective electrodes.Current paths exist between electrode elements of electrode 48 andcorresponding electrode elements of electrode 50. Referring to FIG. 4B,current paths between corresponding electrode elements 62 and 64 areindicated at 66. Each such current path represents a path current flowbetween corresponding electrode elements of electrodes 48 and 50.Current flows along the current paths 66 when a voltage potential isapplied across the electrodes 48 and 50, and corresponding electrodeelements are electrically connected.

In certain applications, corresponding electrode elements of electrodes48 and 50 are electrically connected when immersed in an electrolyticmedium, such as blood. When the electrode elements are electricallyconnected by the medium, there is maximum current flow. When anelectrode element is in contact with a tissue surface, the current pathbetween the electrode elements passes through the tissue surface, whichmay have a much higher resistance. By monitoring the current betweenelectrode elements 48 and 50, the electrodes may be employed as sensorsto detect contact between the distal end probe 42 and the tissuesurface.

In various embodiments, the electrodes 48 and 50 are electricallyconnected to circuitry, such as that described with reference to thecontrol unit 28 of FIG. 1, through conductors 58 and 60. The circuitrymeasures the extent to which the current paths between correspondingelectrode elements are blocked or enabled by measuring total currentflow across the electrodes 48 and 50 when a voltage is applied acrossthe electrodes 48 and 50.

FIG. 5A is a diagram showing the distal end probe 22 in partial contactwith the tissue surface 18. Inner electrode 48 and outer electrode 50are also shown schematically. When the distal end probe 22 contacts thetissue surface 18 at an angle other than 90.degree., as shown in FIG.5A, the electrode elements in contact with the tissue surface willconduct relatively little current while the exposed electrode elementsmay remain in contact with a more conductive medium, such as blood. Therelationship between the percentage of the probe face 46 in contact withthe tissue surface and the current through the electrode elements isshown in FIG. 5B. Little or no contact results in maximum current. Theamount of current decreases in the manner shown until complete orsubstantially complete contact is achieved, thus providing an indicationof the amount of contact between the distal end probe 22 and the tissuesurface.

When the distal end probe is guided into place transvascularly, theblood will provide a conductive path between the electrodes 48 and 50and the tissue will provide a relatively less conductive path. In otherembodiments of the invention, however, blood may not provide aconsistent conductive medium between the electrodes 48 and 50 prior tocontact with the tissue. For example, if the distal end probe 22 isintroduced into a relatively dry field, such as the thoracic cavity viaan intercostal incision, little or no current will be conducted betweenthe electrodes 48 and 50 prior to contacting the patient's tissue. Whenthe patient's tissue is contacted, however, the relatively moist tissuesurface may provide sufficient conductivity to establish a detectableincrease in current between the electrodes 48 and 50. Again, theincrease in detected current may be proportional to the surface area ofthe electrodes 48 and 50 in contact with the target tissue surface, butwith current increasing with increasing tissue contact in thiscircumstance. By appropriate modification of the circuitry in thecontrol unit 28 (FIG. 1), the electrodes 48 and 50 can, therefore, beadapted to detect tissue contact as reflected in a drop in current or anincrease in current.

In one embodiment of the distal end probe 22, one or more of theelectrodes 48 and 50 function as physiological sensors. In oneembodiment, the physiological sensors are EKG sensors. The electrodes 48and 50 transmit EKG data to a control unit, such as the control unit 28in FIG. 1, via the conductors 58 and 60. The EKG data is processed anddisplayed. The availability of EKG information with position informationduring a procedure has several advantages. For example, the positioninformation provides a precise origin of the EKG information. Inaddition, when a therapeutic agent is introduced into a target region oftissue, the change in the tissue can be observed in real-time throughthe EKG. The EKG information assists the user in assessing the health oftissue in a prospective target region. For example, a user may discard apreviously chosen target region for injecting an angiogenic agentbecause the EKG information indicates the tissue in the region isinfarcted. Conversely, the user can check the EKG information when thedistal end probe has been positioned and deliver the therapeutic agentif the condition of the tissue is satisfactory per the EKG information.

FIG. 6A is an end view of an embodiment of a distal end probe 68 thatallows the quality of contact between the distal end probe 68 and atissue surface to be sensed. The quality of contact includes degree ofcontact and the angle between the longitudinal axis of the distal endprobe 68 and the tissue surface. The distal end probe 68 includes alumen 71. A probe face 70 (shown in FIG. 6B) of the distal end probe 68includes an outer annular electrode, or sensor, 74, and an inner annularelectrode, or sensor, 72 that includes multiple electrode sections 72 a,72 b, 72 c, and 72 d. The insulators 78 and 76 separate the electrodes72 and 74. The insulator 76 further separates the sections of theelectrode 72 from each other.

As shown in the cross-sectional view of FIG. 6B, the electrodes 72 and74 are electrically connected to circuitry, such as that described withreference to the control unit 28 of FIG. 1, through conductors 80, 82,and 84. The coupling 80 is connected to the electrode 74. Each of theelectrodes 72 a, 72 b, 72 c, and 72 d are connected to a differentcoupling, only two of which (82 and 84) are shown.

Through the conductors 80, 82, and 84, voltages are applied separatelyto each of the electrodes 72 and to electrode 74. Current may flow bestbetween the electrodes 74 and 72 in the areas that are not in contactwith tissue. FIG. 7A illustrates a case in which the distal end probe 68is in partial contact with a tissue surface such that there is an angleof less than 90.degree. between the longitudinal axis of the distal endprobe 68 and the tissue surface. The shaded regions of the electrodes 72indicate contact with the tissue surface. In this case, there iscomplete contact between the lower portion (in the figure) of the planarprobe face 71 and the tissue surface. There is also partial contactbetween the right and left sides (in the figure) of the probe face 71and the tissue surface.

FIG. 7B is a diagram of an embodiment of a display 86. The display 86indicates the angle and degree of contact corresponding to the currentflow as shown in FIG. 7A. Indicators 85 are typical of the 17 indicatorsthat are arranged in two lines that intersect at an indicator 87 asshown. The indicators 85 are arranged to suggest the manner in which theplurality of sensors is arranged on the distal end probe 68. Thearrangement of the indicators generally corresponds to locations on theprobe face 71. A shaded indicator 85 indicates contact between the probeface 71 and the tissue surface at the location of the shaded indicator.An unshaded indicator 85 indicates no contact between the probe face 71and the tissue surface at the location of the unshaded indicator. In oneembodiment, the indicators are lights, such as light emitting diodes(LEDs), and are lit when a corresponding electrode is in contact withtissue. The display 86 allows a user to quickly assess angle and degreeof contact between the probe face 71 and the tissue surface.

In one embodiment of the distal end probe 68, one or more of theelectrodes 72 and 74 function as physiological sensors. In oneembodiment, the physiological sensors are EKG sensors. The electrodes 72and 74 transmit EKG data to a control unit, such as the control unit 28in FIG. 1, via the conductors 80, 82, 84, etc. The EKG data is processedand displayed.

FIGS. 8A-8C are diagrams of an embodiment of a distal end probe 88 thatfacilitates a determination of the angle of contact between the probeface 92 and a tissue surface. The distal end probe 88 furtherfacilitates a determination of a degree to which the distal end probe 88intrudes into the tissue surface. The probe face 92 is rounded, as seenin cross-section in FIG. 8B. Annular electrodes, or sensors, 94, 96, and98 are arranged at increasing radii about a lumen 93. Insulators100,102,104, and 106 separate the electrodes 94, 96, and 98. Theelectrodes 94, 96, and 98 are electrically connected to connected tocircuitry, such as that described with reference to the control unit 28of FIG. 1, through conductors 108,110, and 112. Voltages are separatelyapplied to each of the electrodes 94, 96, and electrode 98 through therespective conductors 108, 110, and 112, creating a current flow inproportion to amount and location of contact between the electrodes andthe tissue surface.

FIG. 8C is a diagram of an alternative electrode configuration. Thedistal end probe 89 includes a lumen 91. An inner annular electrode 95substantially covers the rounded face of the distal end probe 89. Theinner annular electrode 95 is separated from an outer annular electrode99 by an insulator 97. The electrodes 95 and 97 are electricallyconnected to circuitry, such as that described with reference to thecontrol unit 28 of FIG. 1, through conductors 101 and 103.

FIGS. 9A and 9B illustrate an example of one application for the distalend probe 88 and the information provided by the electrodes 94, 96, and98. FIG. 9A shows the distal end probe in contact with the tissuesurface 18. The distal end probe 88 intrudes into the tissue surface 18such that the electrode 94 is in contact with the tissue surface 18, butthe electrodes 96 and 98 are not in contact. FIG. 9B shows two graphsthat each plot current as a function of degree of contact between anelectrode and the tissue surface 18. The curve 112 shows the plot forthe distal end probe intruding into the tissue surface 18 to distanced1. The curve 114 shows the plot for the distal end probe intruding intothe tissue surface 18 to distance d2. Distances d1 and d2 areillustrated in FIG. 8B.

The current levels on the plots for d1 and d2 vary depending on theangle of contact and depth of intrusion of the distal end probe 18. Forexample, an optimal contact would give a low current level at d.sub.1,indicating a good contact angle, and a high level at d.sub.2, indicatinga desired depth of intrusion. Various current levels can indicate acontact angle that is not close enough to 90.degree. and/or a level oftissue intrusion that is too high or too low.

FIGS. 10A and 10B illustrate an embodiment of a distal end probe 116that allows the user to obtain information about the angle of contact ofthe distal end probe 116 with the tissue, and the depth of intrusioninto the tissue. The distal end probe 116, as shown in FIG. 1A, includeselectrodes, or sensors, 120, 122, and 124. Each of the electrodes 120,122, and 124 are annular and arranged concentrically about thelongitudinal axis of the distal end probe 116. Each of the electrodes122, 124, and 126 are divided into four electrode sections (labeled a,b, c, and d) that are each electrically insulated from any otherelectrode section by an insulating material, indicated by shading.

The distal end probe 116, as shown in FIG. 10B, has a rounded probe face118 that includes the electrodes 120, 122, and 124 at distances d.sub.1,d.sub.2, and d.sub.3, respectively, from the distal end of the distalend probe 118. Each of the sections a, b, c, and d of the electrodes120, 122, and 124 are electrically connected to circuitry, such as thatdescribed with reference to the control unit 28 of FIG. 1, throughconductors. For example, the coupling 128 b is connected to theelectrode section 124 b, the coupling 126 b is connected to theelectrode section 120 b, and the coupling 126 a is connected to theelectrode section 120 a.

FIG. 11A illustrates the distal end probe 116 in contact with the tissuesurface 18 such that the electrodes, or sensors, 120, 122, and 124 arepartially in contact with the tissue surface 18, including partialintrusion into the tissue surface 18. FIG. 11B is an embodiment of adisplay with four groups of indicators. The indicators are arranged tosuggest the manner in which the plurality of sensors is arranged on thedistal end probe 116. The arrangement of the indicators generallycorresponds to locations about the distal end probe 116. Each of theindicators is similar to exemplary indicators 122 and 124. Indicators122 are shaded to indicate contact between the distal end probe 116 andthe tissue surface 18. Indicators 124 are not shaded to indicate nocontact between the distal end probe 116 and the tissue surface 18. Inone embodiment, the indicators are lights, such as light emitting diodes(LEDs), and are lit when a corresponding electrode is in contact withtissue. Within each of the four groups of indicators, four indicatorsare in a line with a central indicator 125, indicated as lines 1. Theseindicators indicate the current flow through electrode sections at probedepth d.sub.1 thus indicating contact at depth d1. The four indicatorsin lines 2 indicate the current flow through electrode sections at depthd2. The next four indicators in lines 3 indicate the current flowthrough electrode sections at depth d.sub.3. The display pattern in FIG.11B indicates that the electrode sections at all three depths at anarbitrarily designated “lower” portion of the distal end probe 116 arein contact with the tissue surface, as shown by the shaded indicators.The inner electrode sections on two “sides” of the distal end probe 116adjacent the lower portion are also in contact with the tissue surface.The “upper” electrode sections are not in contact with the tissue, asindicated by unshaded indicators. This display reflects the contactsituation shown in FIG. 11A.

The information displayed as in FIGS. 5B, 7B, 9B, and 11B can be used todetermine when to deliver a drug, or some other therapy, to the tissuethrough the distal end probe. As discussed in more detail below, incertain embodiments of the invention, an injectate is injected into thepatent's tissue only after appropriate surface contact between themedical device and the tissue has been detected.

In one embodiment of the distal end probe 116, one or more of theelectrodes 120, 122, and 124 function as physiological sensors. In oneembodiment, the physiological sensors are EKG sensors. The electrodes120, 122, and 124 transmit EKG data to a control unit, such as thecontrol unit 28 in FIG. 1, via the conductors 128 b, 126 a, 126 b, etc.The EKG data is processed and displayed.

Referring to control unit 28 of FIG. 1, in one embodiment, the controlunit 28 further controls the delivery of a drug or therapy when anappropriate position of the distal end probe with respect to the tissuesurface has been achieved. In one embodiment, the activator 30 receivesdata from the control unit 28, and sends an activation signal to theactuator 24 when the data indicates that the appropriate position of thedistal end probe with respect to the tissue surface has been achieved.The activator 30 is programmable to send the activation signal underspecified conditions, including specified distance from tissue,specified degree of contact with tissue, specified angle of contact withtissue and specified degree of intrusion into tissue. In one embodiment,the activator 30 further includes circuitry for guiding the position ofthe distal end probe via the actuator 24 until a desired contactposition is achieved.

Embodiments Employing Needles

FIGS. 12A, 12B, and 13 illustrate embodiments of distal end probeassemblies for delivering a therapeutic stimulus to tissue. FIG. 12A isa cross-sectional view of a distal end probe 130 that has a roundedcontact surface with a central lumen 132 through which a needle 134 canbe extended. In one embodiment, a therapeutic solution is administeredfrom a reservoir in the actuator 24 (FIG. 1) into the target tissuethrough a lumen (not shown) of the needle 134. The distal end probe 130includes electrodes, or sensors, 136, 138, and 140. The electrodes serveas sensors as previously described with reference to other embodiments,and communicate with a control unit, as previously described, throughconductors 142, 144, and 146.

In FIG. 12A, the distal end probe 130 is in a deployment configurationwith the needle 134 in a retracted position wherein the distal end ofthe needle is received within the lumen 132 of the distal end probe 130.The needle 134 may be axially slidable in the lumen 132 of the distalend probe 130. An operator may control movement of the needle 134 alongthe lumen 132 manually, under control of a control unit (28 in FIG. 1),or through any other means known in the art. FIG. 12B shows the distalend probe 130 in a treatment configuration with the needle 134 advanceddistally into an extended position. In one embodiment, the needle 134may be advanced after the sensors 136-140 detect surface contact with apatient's tissue. This will advance the needle 134 into the tissue,facilitating delivery of a therapeutic stimulus, e.g., injection of atissue-damaging agent to create a cardiac lesion in treating atrialfibrillation.

In various other embodiments, working elements other than needles may beemployed. The working element can retract into the distal end probe inthe lumen, or can be fixed in a position. Various working elements canbe used to perform various therapeutic and diagnostic procedures. Forexample, FIG. 13 is a cross-sectional diagram of a distal end probe 150that includes an optical fiber 154 in a central lumen. The optical fiber154 delivers a pulse of laser light as a therapeutic stimulus. Inanother example, needle 134 acts as an RF electrode causing localizedthermal injury in the tissue surrounding the needle.

In one embodiment, a distal end probe such as 130 or 150 is maneuvered,e.g., at the tip of a catheter, to a selected target site. During thismaneuvering, the user may track the probe fluoroscopically, according toknown methods. When the probe is at or near the target site, the userviews a display, such as the ones previously described, to determine theangle of contact and/or depth of contact between the distal end probeand the tissue surface, and also to monitor physiological data. The usercontinues to position the distal end probe until the desired position isachieved. For example, if the distal end probe encounters a trabecula,attempts to improve the contact area by rotating the catheter shaft oradjusting the axial force applied to the shaft may not significantlyimprove the indicated degree of contact. In this case, the user maysimply move the probe to another region and attempt to position thedistal end probe again. The user may also select a site and positionbased on the physiological data, such as EKG data.

FIG. 14 is a diagram of an embodiment including a distal end probe 160and a working element 162 in a lumen 164. The working element 162 may bea needle for delivering a drug, cells, or creating an injury usingmechanical or other means. In other embodiments, the working element canbe any one of any of a variety of working elements used in conjunctionwith catheters to perform various medical procedures. The distal endprobe 160 includes electrodes, or sensors, 168, 170, and 172. Theelectrodes 168,170, and 172 function similarly to the electrodes 136,138, and 140 described with reference to FIG. 12A. The working element162 is connected to the coupling 174, which transmits physiological datacollected by the working element 162 from tissue the working element isin contact with. In one embodiment, the physiological data is EKG data.The availability of the EKG information from the working element 162along with the position and/or EKG information from the electrodes168,170, and 172 is very useful for obtaining very site-specificinformation about tissue during a procedure. For example, in the case ofnon-transmural infarcts, an infarcted area can be isolated between theendocardium and the epicardium. As the working element progressesthrough the tissue, the EKG signal from the working element gives anaccurate indication of relative tissue health at the site of the workingelement. Thus, information that is not available from the tissue surfacebecomes available. There may be no electrical activity on theendocardium, but as the working element is advanced through the tissue,electrical activity may be detected closer to the epicardium. Hence, atherapeutic agent may be delivered through a needle 162 to treat tissueand the same needle 162 can be used to monitor physiological datapertaining to the tissue as it is being treated.

FIGS. 12-14 illustrate embodiments employing a single needle. It shouldbe understood that the invention may be practiced with a plurality ofneedles. The needles may communicate with a common reservoir ofinjectate, or may be used to deliver different injectates. If theneedles are retractable during deployment, they may be deployedindividually or with a common deployment mechanism. If multiple needlesare employed, they need not all be oriented for deployment distally froma distal end of the injectate delivery device. For example, they may bespaced along a length of an elongate tissue-contacting member (e.g.,member 434 of FIG. 29 or member 454 of FIG. 30) adapted to position theneedles in close proximity to the surface of the target tissue prior todeployment.

Embodiments Employing Needleless Injection

FIG. 15 illustrates a catheter assembly, indicated generally by thereference numeral 212, in accordance with another embodiment of theinvention. The catheter assembly 212 (or even just selected aspectsthereof) can be used instead of the apparatus 14 or 15 of FIGS. 1 and 2,respectively, (or selected aspects thereof in the embodiments discussedabove. Likewise, aspects of the apparatus 14 and 15 may be used inconjunction with the catheter assembly 212 and other embodimentsdiscussed below.

The catheter assembly 212 of FIG. 15 includes a hand unit 214 attachedto a steerable catheter shaft or jacket 216 having a controllablydeflectable distal-end portion, as at 216 a. Steering of the catheterassembly can be accomplished in a variety of ways. For example, thecatheter assembly can include steering components like those disclosedin U.S. Pat. No. 5,876,373, entitled “Steerable Catheter,” to Giba etal.; and/or in U.S. Pat. No. 6,182,444, entitled, “Drug DeliveryModule,” to Glines et al.; and/or in published European PatentApplication No. EP 0 908 194 A2; each of which is incorporated entirelyherein by reference. In one exemplary arrangement, a conventional pullwire (not shown) is secured at a distal tip of the jacket and extendsthrough a wire-guide channel, formed longitudinally through a sidewallof the jacket, to the hand unit, whereat the wire's proximal end iscoupled to a deflection or steering actuator assembly. Rotation of adeflection knob, such as 220, which is threadedly mounted along aforward end of the hand unit, causes the pull wire to be pulledbackward, and/or the jacket to be pushed forward, relative to oneanother, thereby inducing deflection of the distal end of the jacket.Rather than running the pull wire through a channel extending through asidewall of the jacket, another embodiment provides the pull wireextending longitudinally along an interior sidewall of the jacket. Anadvantage of the steerable catheter embodiment of the present embodimentover Giba's steerable catheter is the omission of the third inner tool,housed within the second, steerable catheter of Giba. Embodiments of thepresent invention provide for a unified structure of the tool andsteerable catheter making the device simpler, more easily operated, andless costly to manufacture than Giba's triaxial, or coaxial arrangement.Another embodiment of the invention provides for a single catheterunified system where the jet device is integrated into a steerablecatheter and omitting the outer, non-steering sheath catheter of Giba,discussed above. Alternatively, the inner tool or fiber optic of Gibamay be omitted resulting in a steerable catheter slidably housed withinan outer sheath. Other navigation mechanisms and arrangements, suitablefor use herein, will be apparent to those skilled in the art. Forexample, the catheter shaft or jacket can be configured with a fixedshape (e.g., a bend) at its distal end to facilitate navigation asdescribed in application Ser. No. 08/646,856 by Payne filed May 8, 1996,entirely incorporated by reference herein. Another embodiment of thepresent invention provides for an arrangement that includes a dualsteering mechanism where both the inner and outer catheter are steerablewith either or both catheters steering as a result of either or bothhaving a pull wire or a pre-shaped member. FIG. 25 illustrates a doublesteerable catheter device 1100, having a first outer steerable catheter1102 slidably housing a second inner catheter 1104 having a jetdischarge tip 1106 located on its distal end 1108.

Jacket 216 is dimensioned to be placed in the vasculature of a subjectand navigated therethrough until the distal tip is disposed proximate asurface or wall region of a selected tissue or organ, e.g., within about5 mm from a surface within a heart chamber (such as the endocardial wallwithin the heart's left ventricle). The outer diameter of the catheterjacket is not critical, provided only that it can be navigated to adesired site within a subject body. Suitable catheter jackets range insize, for example, from about 3 French to about 9 French. One preferredcatheter jacket is 7 French. Suitable catheter jackets are availablecommercially, for example as guiding catheters and diagnostic cathetersfrom Bard Cardiology, Cordis, and Schneider Worldwide. Certain preferredjackets from such sources include fixed shapes at their distal end,instead of pull-wire steering mechanisms.

Visualization enhancement aids, including but not limited to radiopaquemarkers, tantalum and/or platinum bands, foils, and/or strips may beplaced on the various components of the catheter assembly, including onthe deflectable end portion 216 a of catheter jacket 216. In oneembodiment, for example, a radiopaque marker (not shown) made ofplatinum or other suitable radiopaque material is disposed adjacent thedistal tip for visualization via fluoroscopy or other methods. Inaddition, or as an alternative, one or more ultrasonic transducers canbe mounted on the catheter jacket at or near its distal tip to assist indetermining its location and/or placement (e.g., degree ofperpendicularity) with respect to a selected tissue in a subject, aswell as to sense proximity with, and/or wall thickness of, the tissue.Ultrasonic transducer assemblies, and methods of using the same, aredisclosed, for example, in published Canadian Patent Application No.2,236,958, entitled, “Ultrasound Device for Axial Ranging,” to Zanelliet al., and in U.S. Pat. No. 6,024,703, entitled, “Ultrasound Device forAxial Ranging,” to Zanelli et al., each of which is incorporatedentirely herein by reference. In one embodiment, for example, twotransducers are angle mounted at the distal tip of the catheter shaft inthe axis or plane of pull-wire deflection. This construction permits anoperator to determine, by comparing signal strength, whether thecatheter tip region is perpendicular to a selected tissue surface orwall. Additionally, this two-transducer arrangement provides an operatorwith information useful for determining an appropriate adjustmentdirection for improving perpendicularity, as compared tosingle-transducer arrangements that, while capable of indicatingperpendicularity by signal strength amplitude, are generally incapableof indicating a suitable direction in which to move the tip to improveperpendicularity. In a related embodiment, third and fourth transducers(not shown) are added, off of the deflection axis, to aid an operatorwith rotational movement and rotational perpendicularity in thenon-deflecting plane of the subject tissue surface. Additional detailsof the just described embodiment are provided in co-pending U.S. patentapplication Ser. No. 09/566,196, filed May 5, 2000, entitled, “Apparatusand Method for Delivering Therapeutic and Diagnostic Agents,” to R.Mueller; incorporated entirely herein by reference. Ultrasonictransducers may, preferably, be substituted with one or more forcecontact transducers as described in U.S. Provisional Patent ApplicationNo. 60/191,610, filed Mar. 23, 2000 by Tom, entirely incorporated byreference herein.

With respect to hand held, open surgery devices, it is often importantto insure that proper contact force is created between the device and atarget tissue before discharging the device. Otherwise, the device mayinadvertently discharge as it is manipulated towards a target tissue, orit may, in the case where too much force is applied, cause perforationof a tissue that is thinned out as a result of distention caused byexcessive force. A force sensing interlock may be incorporated into theinvention thus only permitting discharge when such force is within acertain range, both minimally and maximally. For example, ultrasoundtransducers, force contact transducers, and mechanical interlocks havinga minimal and maximal limit. Consequently, hand held needlelesshypodermic injector devices, such as those described in U.S. Pat. Nos.3,057,349, 3,859,996, 4,266,541, 4,680,027, 5,782,802, each entirelyincorporated by reference herein, lacking interlocks altogether, or onlyproviding interlocks that activate at a minimum threshold force, withoutregard to a maximum force limit, are often inadequate. These handheldneedleless injectors are further limited in that their structure is notamenable for use inside of a patient cavity created by open surgery,thoroscopic or other “portal” procedures. For example, each of thosedisclosures provides for a snub nosed hand-held gun for use against apatient's skin, typically a shoulder region of a human. The presentinvention provides for an elongated jacket portion of the tool tofacilitate reaching inside a remote region of the patient. The tooldistal end may further be angled or bent, either fixedly, or by bendingon demand, or by remote steering of the distal region of the tool. FIG.26 illustrates an open surgical tool where device 1200 has an elongatedjacket portion 1202 having a bend portion 1204, ending in jet tip 1206located at distal end 1212 which is where liquid is ejected whenactuator 1208 is compressed thereby causing a liquid reservoir locatedaround 1210 to deliver fluid to tip 1206 through a fluid conduit notshown.

Internal to the jacket is one or more lumens, extending between thejacket's distal and proximal ends. The lumens serve as passages throughwhich one or more selected agents can pass en route to a selected tissueor organ. In the arrangement of FIGS. 16A-B and 17, for example, asingle lumen, denoted as 222, extends longitudinally through jacket 216.In another embodiment, shown in FIG. 18, a plurality of elongate tubes,such as 224 a-d, extend through a primary lumen 222 defined by thejacket 216. In this latter embodiment, each of the tubes includes aninternal longitudinal conduit or channel, defining a respectivesub-lumen or delivery lumen through which one or more agents can pass.Advantageously, this configuration reduces the dead volume in thesystem. Also, the “on/off” response is optimized, and the pressure limitrequirement for the conduit can be readily met.

Catheter jacket 216 terminates at a distal-end face, indicated generallyat 226, defining one or more narrow outlet ports or orifices, such as228 a-d (FIG. 17). Face 226 is configured with a relatively broad distalsurface region of sufficient area to accommodate a desired number ofoutlet ports such that each port can be placed against, or very close to(e.g., within about 5 mm, and preferably within about 2 mm), a selectedwall or surface region of a target body organ or tissue. Accordingly,one embodiment provides the distal-end face as a generally bluntstructure with a broad distal surface. For example, in FIGS. 16-18, acylindrical plate 232 defines the distal-end face, with the plate havinga distal surface that is substantially planar. Alternatively, the distalsurface can be somewhat curved (e.g., convex). One or more bores extendthrough the plate, between its proximal and distal broad surfaces,defining outlet ports for the passage of selected agents.

The plate 232 can be secured along the distal-end region of the jacket216 in any suitable manner. In one embodiment, for example, the plate isattached directly to the distal tip of the jacket, or in a counterboreformed from the distal tip. Another embodiment, shown in FIGS. 16-18,contemplates the use of an intermediate adapter plug or cap, denoted as234, having a proximal end configured to fit snugly over the outercircumference of a distal-end region of jacket 216. The distal portionof the adapter cap 234 includes an annular counterbore, or steppedregion, configured to receive a peripheral region of the plate 232.Adapter cap 234 can be formed of a suitable plastic material, such aspolyethylene or nylon, or of a metallic material such as stainlesssteel, and bonded to the jacket by heat sealing and/or a conventionaladhesive, or other bonding means. The outlet port(s) can be formed, forexample, by laser boring, photochemical machining, or other suitabletechnique; or the plate and bores can be formed together as a moldedcomponent.

With further regard to the outlet ports, each is adapted forcommunication with one or more of the agent-delivery lumens extendingthrough the jacket. In a preferred embodiment, there are from about 1-12outlet ports (e.g., four, in the illustrated arrangement), each having adiameter of no greater than about 0.025″; and preferably within a rangeof from about 0.00025″ to about 0.020″ (e.g., 0.006″). The size andorientation of each outlet port serves to direct agents passed throughthe catheter lumen(s) in an axial direction, or at an angle no greaterthan about 35 degrees off axis (i.e., relative to the catheter'slongitudinal axis at its distal-end region), in the form of a narrow jetor stream. Axially directed jets or streams can help to maximizepenetration depth, while angled jets or streams can help to increase thetreated area/volume of tissue. Axially directed jets are illustrated inFIG. 16B, wherein four outlet ports are configured to direct an agentpassed through lumen 222 (indicated by the large, darkened arrow)axially into a selected tissue 228 as four separate jets or streams(indicated by the four smaller, substantially parallel arrows).

The outlet ports can be configured to achieve desired jet or spraypatterns by modifying, for example, the port diameter, length and/orinternal shape. The pressure at the port can also be adjusted toinfluence the patterns. Injection streams can be further modified withsecondary injection of additional drug, or a compatible gas, such asCO.sub.2 and/or other absorbable gas. Such a gas can be a goodaccelerator. In addition, a pulsed injection pattern can be employed tocapitalize on tissue recoil effects. In these regards, attention isdirected to FIG. 20A which shows an exemplary agent-delivery port 268and a secondary drug or gas port 272 that meets the delivery port 268 atan angle. Also depicted are several exemplary jet or spray patterns,denoted as “A,” “B” and “C.” Pattern “A” (FIG. 20B) can be achieved bypassing an agent through port 268 under pressure, without the use of asecondary port. Pattern “A” is modified to that of pattern “B” (FIG.20C) by additionally passing an agent or gas through secondary port 272.Pattern “C” (FIG. 20D) is a pulsed spray pattern that can be used totake advantage of tissue recoil effects. This pattern can be achieved bypassing an agent through port 268 as rapid, controlled bursts, withoutthe use of a secondary port.

FIGS. 23A-D are partial side views of the apparatus of FIG. 18 as it isplaced near a tissue T, such as cardiac tissue (FIG. 23A); urged againstthe tissue T (FIG. 23B), thus creating a contact force between thedevice and the tissue T, the application of hydraulic force causingejection of a fluid stream from each outlet port thus propelling thefluid into the tissue T (FIG. 23C); and the removal of hydraulic forceand the retention of fluid by the tissue T within pockets created byhydraulic erosion (FIG. 23D).

In one embodiment, one or more of the agent-delivery lumens and/oroutlet ports includes a valving mechanism operable to regulate fluidflow therethrough. Such an arrangement can be useful, for example, forcontrolling the timing and/or energy of each jet. For example, aquick-action valve can permit controlled, rapid-fire bursts from anoutlet port. In one embodiment, a first burst causes a target tissue torecoil and expand, and a subsequent burst then penetrates the tissuewhile in an expanded state. An exemplary valving mechanism is shown inFIG. 21. Here, an elongate needle plunger 280 has a distal, pointed end282 that is normally urged against a seat seal 284 by a coil spring 286,thereby closing a respective outlet port. Needle 280 can be withdrawnfrom seat 284, against the normal bias of spring 286, by pulling on anactuation line (not shown), manually or otherwise, that connects to aproximal end of the needle, thereby opening the port. In anotherembodiment, a pressure-actuated valving mechanism is employed. Here, thevalve is adapted to open automatically upon reaching a certain,predetermined threshold pressure at the port.

Employing a needleless injection system such as that shown in FIGS.16-19 can reduce the tissue damage often associated with the use ofneedles. Nevertheless, it should be noted that in certain circumstancesa limited amount of tissue damage at or about the injection site may bedesirable. For example, where angiogenic agents are being delivered,tissue injury can be beneficial in creating an environment where theaction of such agents is enhanced. Likewise, when creating a lesion incardiac tissue to treat atrial fibrillation, damaging the tissue duringthe process of injection may enhance lesion formation by the agent beinginjected. Thus, it will sometimes be desired to configure the outletports to produce jet or spray patterns appropriate for effecting adesired amount of tissue damage over a selected area.

In addition to the lumen arrangements described above with respect toFIGS. 16-18, the present invention further contemplates an assemblyincluding one or more elongate tubular elements that can be removablyreceived within a primary lumen defined by an outer elongate sleeve.Each removable tubular element, in this embodiment, defines a sub-lumenor delivery lumen through which one or more selected agents can pass,and includes a distal-end face defining one or more respective outletports. Preferably, each tubular element is adapted to slidelongitudinally through the primary lumen of the elongate sleeve forplacement therein and removal therefrom, as desired.

FIG. 24 illustrates a steerable treatment device 330 in accordance withone embodiment of the invention. In this embodiment, the steerabletreatment device includes a steerable outer sleeve 340 and a deliverycatheter 350. The delivery catheter 350 is slidably received in thelumen of the outer sleeve 340. The delivery catheter may include an endmember 352 defining a plurality of outlet ports 355 for delivery of atreatment fluid to target tissue at a selected treatment site. A distallength 342 of the guide catheter 340 may be steered by the operator,e.g., by means of control wires (not shown), causing it to deflect froma relaxed state (shown in solid lines) to a curved state (shown inphantom lines). The end member 352 of the delivery catheter 350 can bepositioned at a desired location by controlling the axial orientation ofthe guide catheter 340, the curvature of the distal length 342, and theextent of the end member 352 of the delivery catheter 350 beyond thedistal length 342 of the guide catheter 340.

Another embodiment provides such a tubular element extendingside-by-side with a guidewire lumen from a proximal to a distal end ofan elongate sleeve. In still a further embodiment, such a tubularelement is incorporated in a rapid-exchange external-guidewireapparatus. In an exemplary construction of the latter, the tubularelement extends longitudinally from a proximal to a distal end of theelongate sleeve, and runs side-by-side with a guidewire lumen along adistal region (e.g., about 3-5 mm) of the sleeve. For example, thepresent invention can be incorporated in a rapid-exchange apparatussubstantially as taught in U.S. Pat. No. 5,061,273, which isincorporated entirely herein by reference. In yet a further embodiment,such a tubular element is adapted to be removed from a lumen extendinglongitudinally through the sleeve and replaced with a guidewire forfacilitating catheter advancement across an anatomical structure such asa heart valve.

In a further exemplary arrangement, a guidewire lumen is coaxial withone or more delivery lumens, with the guidewire lumen at the center andthe delivery lumens surrounding the guidewire lumen. It is contemplatedthat the guidewire lumen can be used to place other elongated devices,if desired, such as ultrasound sensors to measure wall thickness orpressure sensors to infer contact against a wall.

An agent reservoir can be utilized for holding a selected therapeuticand/or diagnostic agent until delivery. The reservoir can be of anysuitable type. In one exemplary construction, the reservoir isconfigured to hold a fluidic agent (e.g., in liquid form) forintroduction, using a substantially closed system, into anagent-delivery lumen of the jacket. For example, the agent can be heldwithin a chamber provided inside the catheter jacket, or it can beintroduced from an external reservoir (shown schematically as reservoir221 in FIG. 15), such as a syringe or bag, via a conventionalintroduction port located along the hand unit or along a proximal regionof the jacket. In one embodiment, the hand unit is provided with a fixedinternal reservoir for holding a supply of a selected agent to bedispensed. In this embodiment, a supply reservoir, such as a syringe,can communicate with the internal reservoir via a connector provided inthe hand unit's outer housing. The connector is preferably asubstantially sterile connector, such as a standard Luer-type fitting orother known standard or proprietary connector. In another embodiment,the supply reservoir comprises a syringe, pre-loaded with a selectedagent, that can be removably fit into a holding area inside the housingof the hand unit, as taught, for example, in U.S. Pat. No. 6,183,444,entitled, “Drug Delivery Module,” to Glines et al, incorporated entirelyherein by reference.

A pressure control (shown schematically as pump 222 in FIG. 15) isprovided in fluid communication with one or more of the agent-deliverylumens. The pressure control, e.g., a manual or automatic pump, isoperable to establish an elevated pressure within such lumen(s)sufficient to propel an agent placed therein toward, and out of, one ormore of the outlet ports, thereby forming one or more respective fluidjets or streams capable of penetrating a selected tissue disposedadjacent thereto. In one embodiment, the pressure control is ahand-operable syringe-type pump, connected to one or more lumens along aproximal end of the jacket. Commercially available pressure controlsthat can be readily adapted for use herein include, for example, powerinjectors, such as the ACIST Injection System Model CL100 (ACIST MedicalSystems), and inflation devices, such as the ARIA or BREEZE inflationdevices from Schneider/Namic (Glen Falls, N.Y.). Examples of suchinjection devices are disclosed in U.S. Pat. Nos. 4,592,742, 5,383,851,5,399,163, 5,520,639, 5,730,723, 5,746,714, and 5,782,802, each of whichis incorporated entirely herein by reference.

An exemplary method of using the above catheter assembly will now bedescribed, wherein the catheter assembly is used for intra-myocardialdelivery of a selected therapeutic and/or diagnostic agent. Initially,catheter shaft 16 is percutaneously introduced via femoral or radialartery access. Once arterial access is established, the catheter shaftis slid across the aortic valve and into the left ventricle chamber. Thedistal end of the catheter shaft is maneuvered so as to be substantiallyperpendicular to the endocardial wall 228 (FIG. 16B), using fluoroscopicvisualization and/or ultrasound guidance, and pressed into contacttherewith. A selected agent, in fluidic form, is then introduced into aproximal-end region of lumen 222, and the lumen is pressurized. Underthe influence of such pressure, the agent is propelled through thelumen, to and out of one or more outlet ports. In this way, one or morenarrow jets or streams are directed at the endocardial wall.

The depth to which each jet penetrates the tissue being treated maydepend, at least in part, on the pressure at which the fluid isdelivered through the outlet ports and the length of time during whichfluid is delivered. In one embodiment, the operating parameters areselected such that the jets penetrate to a tissue depth of at leastabout 2-10 mm, e.g., about 5 mm. The injection may be carried out over atime period of about 1-15 seconds. In certain embodiments, suitablefluid delivery pressures, i.e., the fluid pressure adjacent the outletports, may be about 20-4,500 psi. Lower delivery pressures (e.g., 100psi or less) may be useful in introducing low viscosity materials in amore superficial portion (e.g., less than 2 mm deep) of the tissue beingtreated. Higher delivery pressures, such as 400 psi or greater may beemployed where deeper tissue penetration is desired.

In one embodiment particularly well suited for treatment of atrialfibrillation, delivery pressures are selected to permit the jets topenetrate the entire thickness of the myocardium. Delivery pressures inexcess of 100 psi, more likely at least about 400 psi, may suffice;delivery pressures of about 600-2,000 psi are expected to work well. Ifthe jets penetrate the entire thickness of the myocardium, atissue-ablating agent may be retained throughout the entire thickness ofthe tissue, creating a fairly precisely positioned lesion which canextend from one surface of the tissue to the opposite tissue surface.

This embodiment of the invention can provide a distinct advantage overprocesses employing needles to inject fluids into the myocardium. If aneedle is used to inject an ablating agent into the myocardium, thefluid will exit the needle at a specific location within the tissuewall. As more fluid is delivered through the needle, the thickness ofthe tissue affected by the delivered fluid will increase. However, thetissue will also tend to diffuse laterally at the same time. As aconsequence, a transmural lesion created with a needle-based injectionmay be significantly wider than necessary. In addition, if the needle isplaced imprecisely with respect to the thickness of the myocardium, astandard volume of fluid may not be sufficient to extend from one tissuewall to the other.

If pressurized fluid jets capable of penetrating the entire thickness ofthe myocardium are used instead of a needle, an operator can be assuredthat the entire thickness of the tissue will be treated with apredetermined fluid volume. By appropriately orienting the jets withrespect to the tissue surface and one another, the width of the affectedtissue can be controlled. For example, orienting the outlet portssubstantially perpendicular to the endocardial wall 228 (FIG. 16B), thejets may define a transmural path that is much more focused than wouldbe achievable with a needle.

Instead of a catheter-type device, the invention can be incorporated inother percutaneous and/or surgical devices. For example, one embodimentcontemplates an endoscope-type device having an elongate shaft with oneor more longitudinally extending lumens extending therethrough. As withthe catheter-type device, the structure defining each lumen (e.g., theendoscope shaft, or one or more tubes extending through the shaft) isconfigured to withstand an elevated pressure (e.g., up to 2000 psi) inthe lumen. Also, like the catheter-type device, a substantially blunt,distal-end face defines one or more outlet ports communicating with oneor more of the lumens, with each of the outlet ports having a diameterof about 0.025″ or less (e.g., 0.006″). A pressure control, such as apump, is provided in fluid communication with one or more of the lumens,operable to establish an elevated pressure within such lumen(s) suchthat an agent placed therein will be propelled toward, and out of, oneor more of the outlet ports, thereby forming one or more respectivefluid jets or streams capable of penetrating a selected tissue disposedadjacent thereto Various other details pertaining to agent delivery aresubstantially like those set forth herein with regard to thecatheter-type device.

In an exemplary use, the endoscope-type device of the invention isintroduced thoracoscopically or through a thoracotomy to directhigh-energy jets at the wall or surface of a selected tissue or organ.For example, one or more high-energy jets can be directed at theepicardial surface of the heart, permitting one or more selected agentsto penetrate the myocardial tissue. The surgical device can incorporatea thoracoscopic camera (e.g., a reusable 5 mm camera) axially mounted toprovide an operator with a suitable field of view through a lens. Thisallows the operator to work through a common trocar access port placed,for example, through a patient's chest wall.

It is noted that the above-described methods are merely exemplary innature. Those skilled in the art will appreciate that the presentinvention provides for the delivery of selected agents to a wide varietyof body organs and regions.

In another embodiment of the present invention, a selected therapeuticand/or diagnostic agent is held within a reservoir at the distal-endregion of an elongate shaft and delivered into a tissue by means ofultrasonic energy. Pertinent portions of an exemplary agent-deliveryapparatus, which can be incorporated in a catheter-type device or anendoscope-type, such as previously described, are shown in FIG. 19.Here, the distal-end region of a catheter-type device is shown, havingan ultrasonic transducer 252 (e.g., a piezoelectric transducer, such asbarium titanate, lead zirconate titanate, or the like) disposed acrosslumen 222. The distal end of the catheter jacket defines a single,relatively large opening, denoted as 256; however, a cap or plug withone or more smaller openings (similar to that described above) can beused instead. The transducer is operable to emit ultrasonic energy, ofappropriate intensity (e.g., up to about 6 watts/cm.sup.2) and frequency(e.g., up to about 20 MHz), along a generally axial direction toward awall or surface region of a selected organ or tissue 228 within asubject body. The energy, so applied, is effective to cause an agent258, held within a holding region near the distal end of the catheterjacket, to move toward and penetrate the tissue wall. In one embodiment,the agent is distributed in a polymer matrix, or other solid orsemi-solid form, within the holding region. The agent is maintained inthe matrix within the holding region until the time of delivery.Alternatively, the agent (e.g., in liquid or semi-solid form) can bemaintained within the holding region until delivery by providing asemi-permeable membrane between the agent and the opening at the distalend of the catheter jacket. Other means for maintaining the agent in theholding region until delivery will be apparent to those skilled in theart.

In another embodiment, a selected therapeutic and/or diagnostic agent isheld within a distal-end region of a catheter or endoscope-type deviceand propelled into a target tissue or organ using a biolisticparticle-delivery or bombardment assembly. In one embodiment, thebiolistic assembly (e.g., a so-called “gene gun” incorporated along adistal-end region of the agent-delivery device) introduces nucleicacid-coated microparticles, such as DNA-coated metals, into a tissue athigh energies. The coated particles can be propelled into the tissueusing any suitable means, e.g., an explosive burst of an inert gas e.g.,(helium), a mechanical impulse, a centripetal force, and/or anelectrostatic force (See, e.g., U.S. Pat. No. 5,100,792 to Sanford etal.; incorporated entirely herein by reference). In an exemplaryembodiment, a spark discharge between electrodes placed near thedistal-end region of the catheter, proximal of a distal-endagent-holding region, is employed to vaporize a water droplet depositedtherebetween, which then creates a shock wave capable of propelling theDNA-coated particles. The technique allows for the direct, intracellulardelivery of DNA. The carrier particles are selected based on theiravailability in defined particle sizes (e.g., between about 10 and a fewmicrometers), as well as having a sufficiently high density to achievethe momentum required for cellular penetration. Additionally, theparticles used are preferably chemically inert to reduce the likelihoodof explosive oxidation of fine microprojectile powders, as well asnon-reactive with DNA and other components of the precipitating mixes,and display low toxicity to target cells (See, e.g., ParticleBombardment Technology for Gene Transfer, (1994) Yang, N. ed., OxfordUniversity Press, New York, N.Y., pages 10-11, incorporated entirelyherein by reference). For example, tungsten and/or gold particlemicroprojectiles can be employed to achieve adequate gene transferfrequency by such direct injection techniques. Alternatively, or inaddition, diamond particles, as well as glass, polystyrene and/or latexbeads can be used to carry the DNA. The DNA-coated particles can bemaintained in the agent-holding region by any suitable means, e.g.,precipitated on the distal face of a carrier sheet suspended across alumen at or near the distal end of the jacket. In this latterembodiment, the propulsion means propels the DNA-coated particles from adistal face of the carrier sheet into a selected target tissue or organadjacent thereto.

It will be appreciated that, especially with regard to catheter-typedelivery apparatus, an agent directed from a distal end of the apparatuswith sufficiently high energy may cause such end to move away from atarget tissue wall or surface. FIG. 22, for example, shows a portion ofa steerable catheter 292 having a distal end positioned adjacent atarget region of an endocardial wall 228 of a patient's left ventricle294.

Arrows “A” and “B” depict an “action-reaction” phenomenon, with (i)arrow “A” representing an injection force provided by one or morehigh-energy fluid jets or streams directed against the wall 228, withthe jet(s) carrying, for example, an angiogenic agent (e.g., “naked”DNA), and (ii) arrow “B” representing a resultant, oppositely-directedforce tending to push the distal tip of the catheter away from theendocardial wall. To counter the latter, means are provided formaintaining the distal end of the catheter proximate the endocardialwall. In the illustrated embodiment, a secondary lumen 296 extendslongitudinally along the catheter and terminates at a distal orifice298, short of the catheter's distal end (e.g., by between about 1-4 cm).An elongate wire 302 is slidably received within the secondary lumen 296and has its distal end attached to the catheter at, or near, thecatheter's distal end. From a remote (proximal) location, wire 302 canbe moved between a retracted position, with the distal region of thewire positioned closely adjacent the catheter (not shown), and anextended position, with a distal region of the wire extended beyond thesecondary lumen's distal orifice so as to bow away from the cathetershaft (shown in FIG. 22). At such extended position, a central region ofthe bowed portion of the wire presses against a back wall of theventricle, as at arrows “E,” thereby causing a distal region of thebowed portion to urge the catheter's distal end toward the target regionof the endocardial wall, as indicated by arrow “C.” In anotherembodiment, a region of the catheter, toward its distal end, isconfigured with a pre-formed (normal) bend of sufficient stiffness orrigidity to maintain the distal tip of the shaft proximate the targetregion of the endocardial wall, notwithstanding such “action-reaction”forces. For example, a reinforced external sleeve can be placed over theregion “D” of the catheter shaft to impart the desired bend along suchregion. Alternatively, the bend along region “D” can be inducible from aremote position.

In general, the apparatus and method of the present invention may employa wide variety of agents, e.g., ranging from active compounds to markersto gene therapy compounds. Exemplary agents, contemplated for useherein, are set forth in U.S. Pat. Nos. 5,840,059; 5,861,397; 5,846,946;5,703,055; 5,693,622; 5,589,466; and 5,580,859, each incorporatedentirely herein by reference. In one embodiment, for example, theinvention is employed to deliver one or more genes (e.g., as so-called“naked DNA”) into cavities formed into the myocardium of a subject.

In one embodiment, wherein the agent includes DNA, controlled-releasepreparations are formulated through the use of polymers to complex orabsorb the selected gene sequence (with or without an associatedcarrier, e.g., liposomes, etc.). The agents can be formulated accordingto known methods to prepare pharmaceutically useful compositions,whereby these materials, or their functional derivatives, are combinedin admixture with a pharmaceutically acceptable carrier vehicle.Suitable vehicles and their formulation are described, for example, inNicolau, C. et al. (Crit. Rev. Ther. Drug Carrier Syst. 6:239-271(1989)), which is incorporated entirely herein by reference. In order toform a pharmaceutically acceptable composition suitable for effectiveadministration, such compositions will contain an effective amount ofthe desired gene sequence together with a suitable amount of carriervehicle.

Additional pharmaceutical methods may be employed to control theduration of action. Controlled delivery may be exercised by selectingappropriate macromolecules (for example polyesters, polyamino acids,polyvinyl, pyrrolidone, ethylenevinylacetate, methylcellulose,carboxymethylcellulose, or protamine sulfate) and the concentration ofmacromolecules as well as the methods of incorporation in order tocontrol release. Another method to control the duration of action bycontrolled release preparations is to incorporate the agent intoparticles of a polymeric material such as polyesters, polyamino acids,hydrogels, poly(lactic acid) or ethylene vinylacetate copolymers.Alternatively, instead of incorporating these agents into polymericparticles, it is possible to entrap these materials in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose or gelatinmicrocapsules and poly(methylmethacylate) microcapsules, respectively,or in colloidal drug delivery systems, for example, liposomes, albuminmicrospheres, microemulsions, nanoparticles, or nanocapsules inmacroemulsions.

In a typical use, the agent will enter at one or more target regionsalong a surface or wall of a selected tissue, and diffuse into thetissue, aided by the action of the jets. Advantageously, the high-energyjets provided herein can be utilized even when the distal end of theapparatus (e.g., a catheter shaft) is highly deflected.

FIGS. 27A and 27B illustrate a distal length of a treatment apparatus360 in accordance with another embodiment of the invention thatincorporates tissue contact sensors and needleless injectioncapabilities. In a manner analogous to the distal end probe 116 of FIGS.10A-B, the treatment apparatus 360 includes a series of sensors 370 a-d,372 a-d, and 374 a-d. These electrodes 370-374 may be arrangedconcentrically about the lumen 362 of the treatment apparatus 360. Thedistal end of the treatment apparatus is rounded to facilitate detectionof the degree of penetration of the treatment apparatus 360 in apatient's tissue. Unlike the probe 116 of FIG. 10, the treatmentapparatus 360 of FIGS. 27A-B includes a distribution plate 364 adjacenta distal end of the lumen 362. This distribution plate 364 may include aplurality of outlet ports 366, similar to the plate 232 and outlet ports228 of FIGS. 16-18. The sensors 370-374 permit an operator to detect,prior to injecting an agent through the outlet ports 366, when thedistal end of the treatment apparatus 360 (and hence the plate 364) isin contact with the tissue to be treated.

FIGS. 28A-C illustrate a treatment apparatus 400 in accordance withanother embodiment of the invention. The treatment apparatus 400comprises an elongate body 410, e.g., a catheter, having an elongateproximal length 412 and a tissue-contacting member 414. A distal end 416of the body 410 may be sealed to prevent fluid delivered through thelumen of the body from exiting the distal end 416. In one embodiment,the tissue-contacting member 414 of the body 410 is relatively rigid andretains the curved shape shown in FIGS. 28A-C. The proximal length 412and the tissue-contacting member 414 may be coplanar. In the illustratedembodiment, which is well suited for thoracic approaches to the exteriorof a patient's myocardium, the proximal length 412 and tissue-contactingmember 414 meet at an angle .theta. of about 90.degree. The angle.theta. can be varied as desired, with a suitable range depending on thenature of the procedure for which the apparatus 400 is employed and themanner in which the targeted tissue is approached.

If so desired, at least a portion of the length of the tissue-contactingmember 414 of the body 410 may be flexible, permitting it to deform fromthe rest configuration. For example, the tissue-contacting member 414may be deformed to pass through a steerable outer sleeve (e.g., sleeve340 in FIG. 24) or an intercostally positioned guide canula, thenresiliently assume the curved rest configuration shown in FIGS. 28A-C.The rest configuration of the tissue-contacting member 414 may beselected as desired to permit it to conform to a surface of the tissueto be treated. For example, the shape shown in FIGS. 28A-C may beadapted to encircle a portion of a junction between a patient'smyocardium and a pulmonary vein.

A plurality of outlet ports 420 a-e are arranged along atissue-contacting inner surface of the tissue-contacting member 414.Each of these outlet ports 420 a-e may be in fluid communication withthe lumen of the body 410 so pressurized jets of fluid (shownschematically by arrows in FIG. 28A) can be directed toward tissue incontact with the tissue-contacting surface 422.

The tissue-contacting member 414 may include a plurality of sensors orelectrodes 425 adapted to detect surface contact between thetissue-contacting surface 422 of the body 410 and a surface of tissue tobe treated. In many of the embodiments noted above, the sensors (e.g.,sensors 94-98 of FIGS. 8A-B) are carried at a distal tip of theapparatus. In the embodiment of FIGS. 28A-C, though, the sensors arespaced along the tissue-contacting surface 422, with one electrode pair420 a-d between each pair of adjacent outlet ports 420 a-e. Byconnecting the sensors 425 to an appropriate control system (e.g.,control system 28 in FIG. 1), the areas of the tissue-contacting surface422 in contact with tissue can be detected and displayed in a suitabledisplay (e.g., display 32 in FIG. 1).

FIGS. 29-32 illustrate alternative embodiments employing differentlyshaped tissue-contacting members. The body 430 of FIG. 29 includes aproximal length 432 and a tissue-contacting member 434 with a generallystraight tissue-contacting surface 436. A plurality of outlet ports 440a-d are spaced along the tissue-contacting surface 436 and a sensor 442a-c or a sensor pair (not shown) may be positioned between each adjacentpair of outlet ports 440.

The body 450 of FIG. 30 includes a proximal length 452 and atissue-contacting member 454 with a generally concave tissue-contactingsurface 456. This tissue-contacting member 454 is similar to thetissue-contacting member 414 of FIGS. 28A-C, but the proximal andtissue-contacting members 452 and 454 are substantially coplanar ratherthan meeting at an angle .theta. as in FIGS. 28A-C. A plurality ofoutlet ports 458 are spaced along the tissue-contacting surface 456 anda sensor 459 may be positioned between each adjacent pair of outletports 458.

In FIG. 31, the body 460 includes a proximal length 462 and atissue-contacting member 464 with an arcuate, generally concavetissue-contacting surface 466. The tissue-contacting member 464 of FIG.31 is similar to the tissue-contacting member 454 of FIG. 30, butextends through a longer arc. A series of outlet ports 468 a-g arespaced along the tissue-contacting surface 466. Three sensors 469 a-care spaced from one another along the tissue-contacting surface 466.

The body 470 of FIG. 32 has a proximal length bending away from theinner, generally concave tissue-contacting surface 476 of the body'stissue-contacting member 474. This can facilitate guiding the tissuecontacting surface 476 into surface contact with the tissue to betreated. A plurality of outlet ports 478 are spaced along thetissue-contacting surface 476 and a sensor 479 may be positioned betweeneach adjacent pair of outlet ports 478.

FIGS. 33-35 illustrate a tissue treatment apparatus 500 in accordancewith another embodiment of the invention. The tissue treatment apparatus500 generally includes a tissue grasping member 510 and at least onefluid delivery conduit 520. The tissue grasping member shown in FIG. 33takes the general form of a pair of medical pliers or a medical clamp.The tissue grasping member 510 may include a pair of grasping actuators512 a-b which are pivotally connected to one another. The distal length514 of each of the grasping actuators 512 a-b is adapted to contacttissue and is desirably formed of a biocompatible material, e.g.,stainless steel. Hence, the grasping actuator 512 a has a tissuecontacting member 514 a and the other grasping actuator 512 b has atissue contacting member 514 b.

As best seen in FIGS. 34 and 35, the tissue contacting member 514 aincludes a tissue-contacting face 516 and a recess 518. The recess 518may take any desired shape. In the illustrated embodiment, the recess518 comprises a generally U-shaped channel which extends along a centerline of the tissue contacting member 514 a. This bisects the face 516into two tissue-contacting surfaces separated by a gap. The gap may bethought of as a plane extending between the two tissue-contactingsurfaces.

In one embodiment of the invention, the tissue-contacting face 516comprises an integral surface of the body of the tissue contactingmember 514. In the embodiment shown in FIG. 35, though, the distal face516 includes a pair of spaced-apart sensors 540. In a manner analogousto the sensors described above, these sensors 540 can be used to detectcontact of the tissue contacting member 514 with the patient's tissueand, if so desired, be used to monitor a physiological aspect of thetissue. In one embodiment, the sensors 540 comprise a pair of electrodeswhich are spaced from one another across the width of the recess 518. Bymonitoring the current flow between these two electrodes 540, one candetect when the face 516 of the tissue contacting member 514 is incontact with the patient's tissue.

The tissue grasping member 510 is adapted to carry at least one fluiddelivery conduit 520 for delivering a fluid to treat a patient's tissue.In the illustrated embodiment, the tissue treatment apparatus 500includes two fluid delivery conduits 520 a-b. The first fluid deliveryconduit 520 a is associated with the first tissue contacting member 514a and the second fluid delivery conduit 520 b is associated with thesecond tissue contacting member 514 b. The fluid delivery conduits 520a-b are in fluid communication with a fluid reservoir (not shown in FIG.33 for purposes of simplicity). The two conduits 520 a-b can beseparately connected to the reservoir. Alternatively, the two conduitscan be joined proximally of the tissue contacting members 514 andcommunicate with the fluid reservoir through a common conduit (notshown). In another embodiment, only one of the tissue contacting members514 a-b includes a fluid delivery conduit 520. The other tissuecontacting member 514 may simply be used to position tissue against thetissue-contacting face 516 of the member 514 carrying the fluid deliveryconduit for treatment, as described below. If one of the tissuecontacting members 514 does omit a fluid deliver conduit 520, thattissue contacting member 514 may have a flat tissue-contacting face 516without a recess 518 to receive the conduit 520.

The fluid delivery conduit 520 a has a proximal length 528 which extendsproximally of the tissue contacting member 514 a and a distal length 522which is received within and extends along the recess 518. (FIG. 34 onlyshows the first tissue contacting member 514 a, but the second tissuecontacting member 514 b may have essentially the same structure.) Thedistal length 522 of the conduit includes a plurality of spaced-apartfluid delivery ports 524. A distal end 526 of the conduit 520 can besealed to direct all of the fluid delivered through the lumen 530 of theconduit 520 through the ports 524.

The recess 518 in the tissue contacting member 514 is adapted to receivethe conduit's distal length 522, or at least the portion of the distallength 522 which includes the outlet ports 524. The distal length 522may be attached to the inner surface of the recess 518 to keep thedistal length 522 in place and orient the ports 524 outwardly from therecess and toward the gap in the face 516 of the member 514. The distallength 522 can be bonded to the inner surface of the recess 518 using abiocompatible adhesive, for example.

The recess 518 is deep enough to permit the outlet ports 524 of thedistal length 522 to be spaced inwardly from the tissue-contacting face516 of the member 514. In the illustrated embodiment, the recess 518 hasa depth which is greater than the outer diameter of the distal length522. The distance between the outlet port 524 and a plane extendingacross the gap in the forward face 516 can be varied as desired. In oneembodiment, the distance is sufficient to ensure that the outlet ports524 will be spaced away from the surface of a tissue being treated. Ifthe tissue being treated is expected to bulge into the recess, thedistance between the port 524 and the face 516 may be greater than ifthe tissue is not expected to bulge very far into the recess 518 duringordinary conditions of use.

FIG. 36 is a schematic cross-sectional view of the tissue treatmentdevice 500 being used to treat a target tissue 544, exemplified in thiscase as tissue of a pulmonary vein 542. While the following discussionfocuses on the use of the tissue treatment apparatus 500 to treat apulmonary may, it should recognize that the apparatus 500 can be used ina variety of other contexts to inject a suitable treatment fluid in anytissue which needs to be treated.

The two tissue contacting members 514 a-b are placed on opposite sidesof the pulmonary vein 542. The grasping actuators 512 a-b are movedtoward one another to bring the tissue-contacting faces 516 of thetissue contacting members 514 a-b against the target tissue 544 of thepulmonary vein 542. In particular, the two opposed tissue contactingmembers 514 are in contact with the target tissue 544 on opposite sidesof the pulmonary vein 542. The fluid delivery ports 524 of each of thefluid delivery conduits 520 are oriented inwardly for the pulmonary vein542. In the illustrated embodiment, the fluid delivery ports 524 of eachconduit 520 are oriented generally toward the other fluid deliveryconduit 520.

As shown in FIG. 36, when the tissue contacting members 514 are urgedagainst the target tissue 544, the distal length 522 of each fluiddelivery conduit 520 a or 520 b is spaced a distance from the surface ofthe target tissue 544. A treatment fluid, e.g., a tissue ablating agent,can be delivered through the conduits 520 a-b and directed out of theports 524 in a series of fluid jets 532. In one embodiment, the pressureof the jets is sufficient to drive fluid through the entire thickness ofthe wall of the pulmonary vein 542, with an excess volume of the fluidbeing delivered into the lumen 546 of the vein 542. In anotherembodiment, the pressure may be reduced to permeate only partiallythrough the thickness of the target tissue 544. Delivering thepressurized fluid jets in this fashion permits the apparatus 500 totreat tissue along lines on opposite sides of the tissue. In the contextof treating a pulmonary vein 542 with a tissue-damaging fluid, this cancreate lesions on opposite sides of the pulmonary vein 524 which extendthrough the entire thickness of both walls.

Spacing the outlet ports 524 from the tissue being treated can beadvantageous in some applications. As noted above, placing the outletports directly against the tissue will yield a focused treatment area.Spacing the outlet ports 524 away from the surface of the tissue willpermit the fluid jets to disperse into a somewhat wider spray pattern,effectively treating a larger tissue area. In the illustratedembodiment, the width of the spray is con strained by contact of theface 516 against the tissue being treated. While this contact need notbe fluid tight, the walls of the recess 518 and the contact between theface 516 and the tissue will limit dispersion of the fluid to a fairlypredictable range. In the context of ablating tissue in treating atrialfibrillation, for example, this will yield a lesion in the tissue havinga predictable, reproducible width.

The embodiment illustrated in FIGS. 33-36, which includes a pair ofopposed tissue contacting members 514 a-b, can also help ensure properpositioning of the outlet ports 524 with respect to the tissue beingtreated. Urging the members 514 a-b toward one another will compress thetissue. Urging the members 514 a-b against the tissue can pull thetissue more taut, reducing the tendency of the tissue to recoil underthe impact of the pressurized jets 532. The force against the tissueshould not be too great, though. In one embodiment, the members 514 urgethe opposite sides of the pulmonary vein 542 toward one another, but notfar enough to come into contact.

FIG. 37A illustrates a tissue treatment apparatus 600 in accordance withanother embodiment of the invention. This tissue treatment apparatus 600includes an elongate body 610 with a manually graspable handle 612adjacent its proximal end and a distal grasping member 620 adjacent itsdistal end. The body 610 and the distal grasping member 620 may be sizedto be introduced into a patient's thoracic cavity through an intercostalincision. The body 610 may comprise a generally rigid tubular memberhaving a lumen extending from the handle 612 to the distal end ofembodiment adjacent the distal grasping member 620. The handle 612 mayinclude an actuator 614 which can be used to move the distal graspingmember 620 between a closed position (shown in FIG. 37A) which may beused when delivering fluid to treat tissue and an open position (notshown) adapted to receive the tissue to be treated. Movement of theactuator 614 can be translated into motion of the distal grasping member620 in any desired fashion, e.g., by means of a flexible cable (notshown). A number of grasping tools adapted for endoscopic procedures areknown in the art and the mechanisms useful in those devices may beemployed to remotely manipulate the distal grasping member 620 of thetissue treatment apparatus 600 of FIG. 37A.

A fluid delivery conduit 630 may be employed to deliver a fluid to treattissue from a reservoir (not shown in FIG. 37A) to a series of distallylocated ports. Although not shown in detail in FIG. 37A, the fluiddelivery conduit 630 may bifurcate distally to provide a pair of distallengths similar to the distal lengths 522 of the fluid conduits 520 a-bin the previous embodiment.

FIGS. 38A and 38B illustrate the distal grasping member 620 in greaterdetail. The distal grasping member 620 includes a first tissuecontacting member 622 a and a second tissue contacting member 622 bwhich can be moved with respect one another between an open position(FIG. 38A) wherein the tissue contacting members 622 are spaced from oneanother and a closed position (FIG. 38B) wherein the tissue contactingmembers 622 are closer to one another. A first branch 632 a of the fluiddelivery conduit 630 may be associated with the first tissue contactingmember 622 a and a second branch 632 b of the fluid delivery conduit 630may be associated with the second tissue contacting member 622 b. Thefirst tissue contacting member 622 a may include a first tissuecontacting face 624 a and the second tissue contacting member 622 b mayinclude an opposed second tissue contacting face 624 b. If so desired,the tissue contacting members 622 may include a recess for receiving theassociated portion of the fluid delivery conduit 630 in a fashiondirectly analogous to that described above in connection with FIGS.34-36.

FIGS. 39A and 39B illustrate an alternative distal grasping member 640that may be used in the tissue treatment apparatus 600 instead of thedistal grasping member 620 shown in FIGS. 38A and 38B. The distalgrasping member 640 may include a first tissue contacting member 642 ahaving a first tissue-contacting face 644 a and a second tissuecontacting member 642 b having an opposed second tissue-contacting face644 b. A first branch 632 a of the fluid delivery conduit (630 in FIG.37A) may be associated with the first tissue contacting member 642 a anda second branch 632 b of the fluid delivery conduit 630 may beassociated with the second tissue contacting member 642 b. The primarydistinction between the distal grasping member 640 of FIGS. 39A-B andthe distal grasping member 620 of FIGS. 38A-B is that the tissuecontacting members 642 of FIGS. 39A-B are inwardly concave, whereas thetissue contacting members 622 of FIGS. 38A-B have a relatively straighttissue contacting face 624. As a consequence, the tissue contactingfaces 624 may be generally parallel to one another in the closedorientation (FIG. 38B), defining a relatively straight gap, whereas thedistal grasping member 640 has a more elliptical space between thetissue contacting faces 644 in the closed configuration (FIG. 39B).

As noted above, the body 610 of the tissue treatment apparatus 600 shownin FIG. 37A may be generally rigid. FIG. 37B illustrates an alternativeembodiment wherein the rigid body 610 is replaced with a more flexiblebody 610′. If so desired, the tissue treatment apparatus may include aflexure control 616 adjacent the handle 612. The flexure control 616 isconnected to the body 610′ such that manual movement of the flexurecontrol proximally or distally (as indicated by the arrows in FIG. 37B)can move the body 610′ between a deflected position (shown in solidlines) and a variety of straighter positions (one of which is shown indashed lines). This can facilitate the proper placement of the distalgrasping member 620 adjacent the target tissue for grasping andsubsequent treatment.

A tissue treatment apparatus 700 in accordance with another embodimentof the invention is illustrated in FIG. 40. This tissue treatmentapparatus 700 includes a body 710 and a distal grasping member 720. Thedistal grasping member 720 may include a first tissue contacting member722 a and a second tissue contacting member 722 b. The first tissuecontacting member 722 a may include an inner tissue contacting face 724a and the second tissue contacting member 722 b may include an innertissue contacting face 724 b. The first tissue contacting member 722 amay be carried adjacent a distal end of an elongate shaft 726 a and thesecond tissue contacting member 722 b may be carried adjacent a distalend of an elongate shaft 726 b. At least one of the two shafts 726 maybe slidably received within a lumen of the body 710. By moving the shaftor shafts 726 within the body 710, the tissue contacting members 722 canbe moved closer toward one another or moved farther away from oneanother. In his fashion, tissue can be selectively grasped between thetwo opposed tissue contacting members 722 for treatment. Although notshown in FIG. 40, a manually graspable handle similar to the handle 612and actuator 614 of FIG. 37A may be carried adjacent a proximal end ofthe body 710 and used to move the shafts 726 with respect one another.In the embodiment shown in FIG. 40, the tissue contacting faces 724 ofthe tissue contacting members 722 may include a plurality of outletports. In one embodiment, the outlet ports are provided in the tissuecontacting member 722 and the tissue contacting members 722 and theirassociated shafts 726 may have a common fluid delivery lumen. This wouldpermit the fluid to be delivered from a reservoir to tissue graspedbetween the tissue contacting members 722. In another embodiment, thetissue contacting members 722 and the shafts 726 may be solid, with aseparate fluid delivery conduit (not shown) having a plurality of portscarried in a recess in the tissue contacting faces 724, similar to thestructure shown in FIGS. 34 and 35.

Methods of Treating Tissue

The apparatus shown in FIGS. 1-40 and detailed above may be used in avariety of procedures, a number of which are outlined above. Severalembodiments of the invention, however, provide methods for treatingcardiac arrhythmia. While reference is made in the following discussionto specific apparatus disclosed in the drawings used to treat cardiacarrhythmia, it should be understood that this is solely for purposes ofillustration and is not intended to limit the scope of the invention. Inparticular, devices other than those shown in the drawings or describedabove may be employed to carry out methods in accordance with theinvention, tissues other than cardiac tissue can be treated, and fluidsother than tissue ablating agents can be injected into the tissue.

As noted above, forming myocardial lesions to create a “maze” whichhelps redirect the cardiac electrical impulse can treat atrialfibrillation. In accordance with embodiments of the invention, injectinga tissue-damaging agent into the myocardium may create such lesions. Thetissue-damaging agent may comprise any injectable fluid agent which,when injected alone or with another agent into cardiac tissue, willcreate a lasting, signal-impeding cardiac lesion suitable for the mazeapproach to treating atrial fibrillation. In certain embodiments, thetissue-damaging agent may comprise a tissue-ablating agent, i.e., amaterial that will lead to a permanent destruction of a function of thetissue, such as effectively conducting cardiac electrical impulses. Thetissue-damaging agent may comprise a liquid, a gas, or both liquid andgas, such as in the embodiment discussed above in connection with FIGS.20A-20D. For example, the tissue-damaging agent may comprise a fluidablating agent selected from the group consisting of alcohols (e.g.,ethanol), hypertonic saline (e.g., 10-25% wt./vol.), thermally-ablatingagents, sclerosing agents, and necrotic antineoplastic agents. Thermallydamaging agents may comprise materials that are biocompatible at or nearbody temperature (e.g., saline, glycerine or ethylene glycol), but areheated so far above or cooled so far below body temperature that theirinjection will induce permanent tissue ablation. Hot injectates whichare hot enough to raise the temperature of the tissue into which it isinjected to 50.degree.-100.degree. should suffice; cold injectates whichare delivered at a temperature below 0.degree. C., e.g., minus0.1-5.degree. C., are expected to work well, too. A variety ofsclerosing agents are known in the art and commercially available,including ethanolamine oleate (e.g., ETHAMOLIN), sodium tedradecylsulfate (e.g., SOTRADECOL), ATHOXYSCLEROL,polyethyleneglycolmonododecylether (e.g., POLIDOCANOL), sodiummorrhuate, and hypertonic saline with dextrose (e.g., SCLERODEX). Knownantineoplastic agents with tissue necrotic effects include CISPLATIN,DOXORUBICIN and ANDRIAMYCIN, each of which is commercially available.

The tissue-damaging agent may be delivered through an injectate deliverydevice that an operator can control from a position outside thepatient's body. For example, the catheter assembly 212 of FIG. 15 may beemployed to inject the agent from the reservoir 221 into the patient'stissue. A tissue-contacting portion of the injectate delivery devicewill be guided within the patient's thoracic cavity into proximity withthe selected region of the heart for treatment. For example, catheterassembly 212 can be introduced into a patient's femoral artery and thecatheter shaft may be passed through the aortic valve and into the leftventricle chamber. The distal end 226 of the catheter 216 may bemaneuvered using fluoroscopic and/or ultrasound guidance, as notedabove. Alternatively, the heart may be approached through an intercostalincision and the delivery device can be positioned or guided within thethoracic cavity. If so desired, the operator may position an endoscopewithin the thoracic cavity to see the location of the delivery devicewith respect to the heart.

The tissue-contacting portion of the delivery device may then be broughtinto surface contact with the tissue surface of the patient's cardiactissue. For example, the distal face 226 of the catheter assembly 212(see, e.g., FIG. 18) may be brought into contact with the tissue surfaceT, as illustrated in FIG. 23 b. As illustrated in FIGS. 28-32, however,devices in accordance with other embodiments of the invention employelongate tissue-contacting areas and merely urging the distal tip of thedevice against the tissue may not bring the intended tissue-contactingarea against the tissue. For example, the body 410 of FIGS. 28A-C may beguided adjacent the heart with the tissue-contacting member 414deflected (e.g., straightened) from its relaxed state. Once thetissue-contacting member 414 is determined to be in the desiredposition, the operator may allow the tissue-contacting member 414 torelax and more closely conform to the tissue surface.

If so desired, the agent may be injected into the cardiac tissue withoutseparately confirming appropriate contact between the delivery deviceand the tissue. In other embodiments of the invention, however, surfacecontact between the tissue-contacting portion of the delivery device andthe cardiac tissue surface is detected before the agent is injected intothe tissue. Appropriate surface contact may be detected in any desiredfashion. In embodiments of the invention, surface contact may bedetected by supplying an excitation voltage to a plurality of electrodespositioned on the tissue-contacting portion of the body and measuring alevel of at least one current conducted by the plurality of electrodes,as discussed above.

For example, contact between the distal end probe 130 of FIG. 12A andthe tissue surface can be can be detected using the sensors 136, 138,and 140 and monitoring the display (32 in FIG. 1) until appropriatesurface contact is indicated on the display. Once appropriate surfacecontact is detected, the needle 134 can be advanced distally into thetissue (not shown in FIG. 12) and the agent can be injected through theneedle 134. If a needleless delivery device such as that shown in FIGS.28A-C is used, surface contact between the tissue and thetissue-contacting surface 422 can be detected using the sensors 425 and,thereafter, the agent can be injected as a series of jets from theoutlet ports 420 a-e.

As noted above, some embodiments of the invention well suited fortreating atrial fibrillation employ pressurized jets of fluid to injecta tissue-ablating agent into the tissue. Fluid delivery pressures may beon the order of 400 psi or higher, e.g., 600-2,000 psi. By selectingpressure and other operating parameters, the jets may be adapted topenetrate 2 mm or more into the cardiac tissue. In one usefulembodiment, the jets are adapted to pass through the entire thickness ofthe myocardium, creating a relatively focused transmural lesion, asdiscussed above. In such an embodiment, a quantity of thetissue-ablating agent may pass into the patient's bloodstream (forinjection into the heart from an external delivery device) or into thethoracic cavity into contact with other organs or tissue (for injectionsfrom outlet ports positioned in the interior of the heart). In suchembodiments, it may be advantageous to select a tissue-ablating agentthat is effective to damage the cardiac tissue in which it is received,but is not overly deleterious to the patient if it enters thebloodstream, for example. For example, ethanol, hypertonic saline andhot saline may all effectively ablate cardiac tissue to create atransmural lesion, but reasonable excess fluid volumes may be introducedinto the patient's bloodstream without significant adverse consequences.

By way of example only, one embodiment that has been found to functionacceptably employs five spaced-apart outlet ports with diameters ofabout 0.004-0.008 inches. Delivering about 1 ml of ethanol at a deliverypressure of about 1000-2000 psi adjacent the outlet ports creates atransmural lesion in atrium walls having a thickness of about 3-8 mm.These operating parameters may be suitable for penetrating entirelythrough even thicker walls, as well.

As noted above, embodiments of the invention permit physiologicalproperties of a tissue (e.g., EKG) to be measured. If so desired, such adevice may be employed to measure the physiological properties of thecardiac tissue on a real-time basis to monitor effect of thetissue-damaging agent on the cardiac tissue, helping ensure that anappropriate cardiac lesion is created. For example, the needle 162 ofFIG. 14 may be used both to deliver the agent and to collect EKG dataindicative of the state of the tissue adjacent the needle 162. Thisallows an operator to ensure that a desired tissue effect is achievedbefore terminating the procedure or moving on to another location forfurther treatment.

The medical device may have a relatively small tissue-contacting surfacedelivering tissue to a relatively focused tissue volume (e.g., thedistribution plate 364 of the treatment apparatus 330 of FIGS. 27A-B).If so, a lesion of the desired length may require a series of injectionsat spaced-apart locations along the tissue surface. Repeatedrepositioning of the device may be reduced, if not eliminated, byemploying a device with an elongate tissue-contacting member, such asthe embodiments of FIGS. 28-32.

Another embodiment provides a method of treating tissue which involvesurging two opposed tissue-contacting members against the tissue. FIGS.41-45 schematically illustrate selected applications of this embodimentto ablate tissue in treating cardiac arrhythmia. These drawingsschematically illustrate a tissue treatment apparatus 600′ similar tothat shown in FIG. 37A, but with the tissue grasping member 620 replacedwith the tissue grasping member 640 shown in FIGS. 39A-B.

As shown in FIG. 41, the tissue treatment apparatus 600′ may bepositioned within a thoracic cavity adjacent the heart 800. The distallypositioned tissue grasping member 640 may be guided toward one of thepulmonary veins 820 a-d, e.g., pulmonary vein 820 a. Positioning thetissue grasping member 640 in an open position, wherein thetissue-contacting members 642 are oriented more away from one anotherthan in the closed position (FIG. 39B), provides an area between the twotissue-contacting members 642 within which the pulmonary vein 820 a canbe received. With the pulmonary vein 820 a received between thetissue-contacting members 642, the tissue-contacting members 642 can bemoved toward one another and into engagement with a tissue surface ofthe pulmonary vein 820 a.

Although FIG. 36 schematically illustrates use of the tissue treatmentapparatus 500 of FIGS. 33-35, the arrangement of the tissue-contactingmembers 642 when brought into contact with the pulmonary vein 820 a maylook much the same in cross-section as the arrangement shown in FIG. 36.In particular, the two tissue-contacting members 642 may contact thetarget tissue 544 along a plane through the target tissue, which may bethought of as a plane extending between the opposed sets of outlet portsin the fluid delivery conduit 630 (conduits 520 a-b are shown in theembodiment of FIG. 36). In a modification of this environment, thetissue-contacting members are instead brought into contact with a targetlocation on the atrium of the heart 800 proximal of the pulmonary veinat a location wherein the pulmonary vein 820 a can be electricallyisolated from the rest of the heart.

In some embodiments, the tissue-contacting members 642 may be urgedagainst the target tissue (544 in FIG. 36) of the pulmonary vein 820 awith sufficient force to deform the pulmonary vein 820 a. This will urgesegments of the pulmonary vein wall located on opposite sides of thepulmonary vein 820 a toward one another. This can effectively grasp alength of the pulmonary vein 820 a, holding the target tissue in arelatively stable position for treatment with a treatment fluid, e.g., atissue-ablating fluid. If so desired, the wall segments may bejuxtaposed with respect to one another, yet remain spaced from oneanother. This permits the blood to continue to flow through thepulmonary vein 820 a in a minimally invasive procedure and avoids unduedamage to the intima of the pulmonary vein's lumen.

A treatment fluid may then be delivered through the fluid deliveryconduit 630 of the tissue treatment apparatus 600. If the treatmentfluid comprises a tissue-ablating fluid, this will simultaneously ablatea line of tissue on each side of the wall of the pulmonary vein 820 a toform a transmural lesion along a length of the wall. The length of thislesion will depend on the length of the tissue-contacting members 642and the positioning of the outlet ports on the fluid delivery conduit630 carried by the tissue-contacting members 642. FIG. 42 illustrates alesion 830 a that extends only along a portion of the wall of thepulmonary vein 820 a.

This partial lesion 830 a may be insufficient to effectivelyelectrically isolate the pulmonary vein 820 a from the atrium of theheart 800. To better isolate the pulmonary vein 820 a, the tissuetreatment apparatus 600 may be repositioned so a portion of thepulmonary vein 820 a which remains untreated is positioned between thetissue-contacting members 642 of the tissue grasping member 640. Asecond lesion may be formed in much the same fashion as lesion 830 a.This second lesion may adjoin the first lesion 830 a to form a longer,effectively continuous lesion. This process can be repeated until theresultant series of lesions forms a relatively continuous lesion 830that substantially circumscribes the pulmonary vein 820 a, as shown inFIG. 43. Each of the four pulmonary veins 820 a-d can be treated in muchthe same fashion to effectively electrically isolate the pulmonary veins820 from the atrium of the heart 800.

FIGS. 44 and 45 schematically illustrate a slightly different adaptationof this embodiment, wherein a lesion is formed in the atrium to isolateto pulmonary veins 820 a-b from the atrium. In the embodiment shown inFIG. 44, much the same distal grasping member 640 of the tissuetreatment apparatus 600 is illustrated. In this embodiment, though, thedistal grasping member 640 is larger than the distal grasping membershown in FIGS. 41 and 42, permitting a lesion 840 to be formed in asingle ablating step rather than requiring a series of separateablations. As in the embodiment discussed above in connection with FIGS.41-43, the tissue-contacting members 642 may be urged into contact withthe target tissue of the atrium. The opposed inner surfaces of the wallof the atrium may be brought closer together for the urging force of thetissue-contacting members 642 and an ablating fluid may be deliveredthrough the fluid delivery conduit (630 in FIG. 37A) to ablate atrialtissue, creating the lesion 840.

Various embodiments of the invention have been illustrated anddescribed. Many alternatives, modifications and variations not shown ordescribed are within the scope of the invention, and are available toone of ordinary skill in the art.

1. A method of treating cardiac arrhythmia comprising: positioning atissue grasping member adjacent a target tissue of a vessel, the targettissue having two spaced-apart wall segments, wherein the tissuegrasping member comprises at least first and second opposed tissuecontacting members each having first and second tissue contactingsurfaces spaced apart from one another to define a gap therebetween, andeach further having a fluid delivery conduit disposed in the gap andspaced apart from the target tissue; moving the opposed tissuecontacting members of the tissue grasping member toward one another todeform the target tissue such that the wall segments are moved closerto, but remain spaced from, one another, such that blood flow throughthe portion of the vessel deformed by the tissue contacting members issubstantially unconstricted; and ablating target tissue in contact withthe tissue contacting members to create a lesion extending through bothwall segments.
 2. The method of claim 1, wherein the first and secondopposed tissue contacting members are pivotally connected to oneanother.
 3. The method of claim 1, wherein the first tissue contactingmember includes a tissue contacting face and a recess comprising agenerally U-shaped channel extending along a center line of the firsttissue contacting member.
 4. The method of claim 3, wherein the tissuecontacting face includes a pair of sensors spaced apart from one anotheracross the recess and configured to detect contact of the first tissuecontacting member with the target tissue.
 5. The method of claim 4,wherein contact of the first tissue contacting member with the targettissue is detected by monitoring current flow between the pair ofsensors.
 6. The method of claim 1, further comprising: delivering atreatment fluid through the fluid delivery conduit to the target tissue.7. The method of claim 6, wherein the treatment fluid is directed out ofthe fluid delivery conduit in a series of jets.
 8. A method of treatingcardiac arrhythmia, comprising: juxtaposing two spaced-apart wallsegments of a pulmonary vein adjacent a heart atrium along a firstplane; ablating tissue in the two spaced-apart wall segments along thefirst plane with an ablating member to form a first lesion along a firstlength of each wall segment; after ablating tissue alone the firstplane, repositioning the ablating member a first time; juxtaposing thetwo spaced-apart wall segments along a second plane; and ablating tissuein the two spaced-apart wall segments along the second plane with theablating member to form a second lesion along a second length of eachwall segment, the second length adjoining the first length.
 9. Themethod of claim 8, further comprising: after ablating tissue along thesecond plane, repositioning the ablating member a second time;juxtaposing the two spaced-apart wall segments along a third plane; andablating tissue in the two spaced-apart wall segments along the thirdplane with the ablating member to form a third lesion along a thirdlength of each wall segment.
 10. The method of claim 8, wherein thefirst and second lengths at least substantially circumscribe thepulmonary vein.
 11. The method of claim 8, further comprising:repositioning the ablating member; and ablating tissue to form at leastone additional lesion which, together with the first and second lengths,forms a series of lesions which at least substantially circumscribes thepulmonary vein.
 12. The method of claim 8, wherein the ablating memberincludes a first tissue contacting member, a second tissue contactingmember pivotally connected to the first tissue contacting member, and afluid delivery conduit.
 13. The method of claim 12, further comprising:delivering a treatment fluid through the fluid delivery conduit to thetwo spaced-apart wall segments.
 14. The method of claim 13, wherein thetreatment fluid is directed out of the fluid delivery conduit in aseries of jets.
 15. A method of treating cardiac arrhythmia, comprising:bringing opposed walls of a cardiac vessel closer together, but not incontact with one another, along a distance within a plane, such thatblood flow from the cardiac vessel into a heart atrium is substantiallyunconstricted; and ablating tissue in the opposing walls along the planeto form a corresponding line of ablated tissue through the opposedwalls.